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PREDISPOSITION TO ABERRANT PERCEPTIONS IS RELATED TO A
HYPEREXCITABLE VISUAL CORTEX EVEN IN NON-CLINICAL GROUPS: NEW
EVIDENCE FROM A tDCS BRAIN-STIMULATION STUDY.
Takahashi, Chie (1) | Braithwaite, Jason J. (2)
Striped patterns, with a spatial frequency of approximately 3 cycle-per-degree of visual angle,
can provoke visual discomfort and induce phantom visual distortions and/or somatic sensations
in susceptible individuals. These phenomena are collectively known as ‘pattern-glare’ and are
thought to reflect increases in cortical hyperexcitability. We present the first study to explore
multi-sensory hallucinations in healthy individuals predisposed to anomalous perceptual
experiences by manipulating the level of excitability in the visual cortex via transcranial Direct
Current Stimulation (tDCS). Sixty participants completed questionnaire measures indexing their
predispositions to specific anomalous perceptions. They also took part in a computer-based
pattern-glare task devised to examine the degree of cortical hyper-excitability. They viewed
gratings known to be visually irritable (and non-irritable baseline gratings) across three separate
tDCS sessions (sham /anodal / cathodal) applied over the visual cortex (site Oz reference site
Cz). Observers who were predisposed to experience aberrant perceptions and hallucinations
reported more visual distortions, relative to a control group, when viewing the irritable gratings
even under sham conditions. Interestingly, these participants also reported significantly more
visual distortions under excitatory stimulation of the visual cortex. Conversely, they showed no
reliable effects under the inhibitory stimulation of the same brain regions. There were no
effects for any baseline stimuli. Taken together, these findings provide the first evidence yet
that the visual cortex is hyperexcitable in non-clinical groups predisposed to anomalous
experiences and hallucination.
[This research was funded by a grant from the Leverhulme Trust, awarded to Dr. Jason
Braithwaite: RPG-2012-500]
(1) School of Psychology - University of Birmingham - United Kingdom | (2) School of Psychology University of Birmingham - UK
Email: [email protected] | [email protected]
Presenter and Poster Info
Takahashi Chie | [email protected]
Sunday, 13th September
DOPAMINE RECEPTOR SIGNALLING AND REACTIVATION OF A
RECONSOLIDATING FEAR MEMORY
Cahill, Emma (1) | Everitt, Barry, J (1) | Milton, Amy, L (1)
Memories are not permanently stable once consolidated; rather, when retrieval is induced by
exposure to a reminder cue, the active memory is rendered labile by a destabilisation process.
Post-traumatic stress disorder is thought to involve maladaptive persistent memories. A novel
therapeutic strategy is to disrupt the memory, when in the active state, with the use of
‘amnestic agents’ targeting specific neurochemical processes. Fear reminders engage the
dopamine system, but the contribution of dopamine signalling to the retrieval and
destabilisation of fear memory is not fully understood.
We performed a combination of behavioural testing using Pavlovian fear conditioning and
molecular analysis in rodents. The reactivation of a cued fear memory induced activation of
the MAPK pathway and Extracellular Regulated Kinase (ERK) in the baso-lateral amygdala, and
not it other brain regions as investigated by Western blotting for the phosphorylated form of
ERK. We analysed the regulation of this pathway, post memory reactivation, downstream of
glutamate and dopamine receptors.
The results will further our understanding of how to achieve diminution of intrusive and
maladaptive memories, by identifying molecular mechanisms downstream of dopamine
receptor signalling for retrieval and destabilisation of memories.
(1) Dept of Psychology - BCNI - University of Cambridge- UK
Email: [email protected]
Cahill Emma | [email protected]
Monday 14th September
BLOCKING CORTICAL GABAA RECEPTORS IMPAIRS SOCIABILITY
Paine, Tracie, A (1) | Swedlow, Nathan (1) | Swetschinski, Lucien (1)
Background: Schizophrenia is a chronic, often debilitating, disorder characterized by positive,
negative and cognitive symptoms. Negative symptoms, including asociality and anhedonia, are
not adequately treated by currently available medications and appear to contribute to poor
outcomes of people with schizophrenia. Post-mortem analyses find reduced expression of GAD
67> (a GABA synthesis protein) and GAT 1 (a GABA reuptake transporter) in the prefrontal cortex
(PFC) of individuals diagnosed with schizophrenia; changes in these proteins suggest decreased
PFC GABA function in schizophrenia. The goal of the current experiment was to determine if
decreasing cortical GABA function is sufficient to cause behavioral changes reminiscent of the
negative symptoms of schizophrenia.
Methods: Rats were implanted with guide cannulae aimed at the medial PFC. Over the course
of 2 weeks rats were tested on a battery of tests: the social interaction test, the social
preference test and the sucrose intake test. Prior to each test rats where infused with either
bicuculline (0.0, 12.5, or 25.0 ng/0.5 μl/side) or L-allylglycine (0.0, 5.0, or 10.0 μg/0.5 μl/side).
Results: Intra-cortical infusions of the GABA A receptor antagonist bicuculline (12.5 or 25 ng/0.5
μl/side), but not the GABA synthesis inhibitor L-allylglycine, decreased both the number of
social interactions and the time spent engaged in social interactions. Similarly, bicuculline (25
ng/0.5 μl/side), but not L-allylglycine, infusions reduced the rats’ social preference. Neither
drug affected sucrose preference.
Discussion: Blockade of GABA A receptors, but not inhibition of GABA synthesis, decreased
sociability. This effect cannot be explained by a reduction in the intrinsic rewarding property
of social interactions. These results are support our previous findings that blockade of GABA A
receptors, but not GABA synthesis, causes schizophrenia-like cognitive symptoms (i.e.,
impaired attention and decision-making). Combined these data suggest that reduced activation
of GABA A receptors, rather than reduced synthesis per se, leads to schizophrenia-like changes
in behavior.
(1) Oberlin College - USA
Email: [email protected] | [email protected] | [email protected]
Paine Tracie A | [email protected]
DISSOCIABLE EFFECTS OF METHYLPHENIDATE ON INTERNALLY AND
EXTERNALLY DRIVEN EFFORT
Morris, Laurel (1) | Chang-Webb, Yee, Chien (1) | Cooper, Ella (2) | Harrison, Neil (2) |
Voon, Valerie (1)
Motivation can be described on several levels, from neuro-pharmacological (dopaminergic
striatal reinforcement, orbitofrontal valuation, lateral prefrontal executive control), to
behavioural (action choice, approach and avoidance), to psychological (goal orientation,
expectation and self-regulation). Mental and physical effort both require incentive motivation,
sharing a common ‘motivational node’ in the ventral striatum. Indeed, mesolimbic
dopaminergic systems have been linked to wanting rather than liking and effort-based decisionmaking. Methylphenidate is a psychostimulant primarily used to treat ADHD, via striatal
dopaminergic modulation but has also been shown to have some efficacy in the treatment of
substance abuse, possibly via cortical dopaminergic modulation.
An interesting question is the distinction between intrinsic and extrinsic motivation, with little
convincing evidence to support dissociable neural mechanisms. Using a novel effort-discounting
task, we distinguish internally generated versus externally generated mental effort for reward
in 28 healthy volunteers. Individuals were instructed to perform a mental effort task and were
then asked about their willingness to perform this mental effort for varying amounts of reward
in a self-generated or explicit manner. We further examine how methylphenidate affects each
condition in a double-blind placebo controlled pharmacological challenge study.
We report a significant drug x condition interaction. Post-hoc analysis revealed that individuals
were significantly more likely to perform mental effort when explicitly asked and less likely
when it was internally generated. However, on methylphenidate, individuals were less willing
to work in the implicit condition and more willing to work in the explicit condition. We highlight
dissociable effects of methylphenidate on internally and externally generated effort motivation.
Together, the findings inform the use of methylphenidate in the management of ADHD and
substance use disorders.
(1) University of Cambridge- UK | (1) University of Cambridge - UK | (2) University of Sussex - UK | (2)
University of Sussex - UK | (1) University of Cambridge - UK
Email: [email protected] | [email protected] | [email protected] | [email protected] |
[email protected]
Morris Laurel | [email protected]
EFFECTS OF ACUTELY ADMINISTERED ADIPOKINETIC HORMONE IN
DEPRESSION, ANXIETY AND PAIN
Mutlu, Oguz (1) | Ulak, Guner (1) | Celikyurt, Ipek, K (1) | Akar, Furuzan (1) | Erden, Faruk
(1) | Tanyeri, Pelin (2)
A great variety of processes in insects is known to be influenced or regulated by neuropeptides.
These peptide hormones are products of neurosecretory neurons located in the corpora cardiaca,
neuroendocrine glands attached to the brain. One of the major neuropeptide groups is the
adipokinetic (AKH) peptides. They control fat, carbohydrate and protein metabolism. The aim
of this study was to investigate the effects of Anax imperator AKH (Ani-AKH), Locusta migratoria
AKH (Lom-AKH) or vehicle (saline with %1 DMSO) administered acutely on depression, anxiety,
pain and locomotion in the forced swimming (FST), elevated plus maze (EPM), hot plate and
locomotor activity tests. In the locomotor activity test, Lom-AKH (2 and 4mg/kg) didn’t alter
total distance moved and speed of the animals while Ani-AKH (4 mg/kg) (p<=0.05) significantly
decreased total distance moved and speed of the animals. In the hot plate test, Lom-AKH (2
and 4mg/kg) didn’t alter latency for the first time licking their hindpaws while Ani-AKH (1 and
2 mg/kg) (p<=0.05) significantly increased latency for the first time licking their hindpaws. In
the EPM test, Lom-AKH (2 and 4mg/kg) didn’t alter time spent in the open arms and Ani-AKH
(0.5 mg/kg) (p<=0.05) significantly increased time spent in the open arms while Ani-AKH (1
mg/kg) (p<=0.05) increased open arm/total arm entries. In the FST test, Lom-AKH (4mg/kg)
(p<=0.05) and Ani-AKH (0.25 and 0.5 mg/kg) (p<=0.01) significantly diminished immobility time
compared to control group. Our study showed that both Lom-AKH (4mg/kg) and Ani-AKH exert
antidepressant effects. Ani-AKH had also anxiolytic and analgesic effects while Lia-AKH had no
effect on anxiety and analgesy when administered acutely.
(1) Department of Pharmacology - University of Kocaeli - Turkey | (2) Department of PharmacologyUniversity of Sakarya-Sakarya-Turkey
Email: [email protected] | [email protected] | [email protected] |
[email protected] | [email protected] | [email protected]
Mutlu Oguz | [email protected]
EFFECTS OF ATYPICAL ANTIPSYCHOTICS ON DEPRESSION, ANXIETY-LIKE
BEHAVIOUR, AND PAIN
Mutlu, Oguz (1) | Ulak, Guner (1) | Celikyurt, Ipek, K. (1) | Akar, Furuzan (1) | Erden, Faruk
(1) | Tanyeri, Pelin (2)
Depression and anxiety is frequently seen in many schizophrenic patients and may be further
aggravated or diminished by antipsychotic treatments. Atypical antipsychotics are known to
possess more beneficial effects on emotional dysfunction in schizophrenia compared to classical
antipsychotics. Olanzapine, clozapine, risperidone and sertindole are frequently used
antipsychotics in the clinics. The aim of this study was to investigate the effects of these drugs
on depression-, anxiety-like behaviors and pain in naive mice, using the forced swiming test
(FST), elevated plus maze (EPM) and hot plate (HP) tests, common and well-known tests to
evaluate depression-, anxiety-like behaviour and analgesy. Mice were treated chronically with
olanzapine (1 and 2 mg/kg), clozapine (1.25 and 2.5 mg/kg), risperidone (0.25 and 0.50 mg/kg),
sertindole (1.3 and 2.5 mg/kg) for 15 days and the drugs were also administered
intraperitoneally 60 min before the tests.
Our study revealed that (1) In the FST test, clozapine (2.5 mg/kg), risperidone (0.5 mg/kg) and
sertindole (1.3 and 2.5 mg/kg) significantly decreased immobility time while olanzapine had
no significant effect. (2) In the EPM test, olanzapine (2 mg/kg), clozapine (1.25 and 2.5 mg/kg),
risperidone (0.50 mg/kg) significantly increased time spent in open arm’s and also increased
open arm entries while sertindole had no significant efffect (3) In the hot plate test, olanzapine
(2 mg/kg), clozapine (1.25 and 2.5 mg/kg), risperidone (0.50 mg/kg) and sertindole (2.5 mg/kg)
significantly increased the latency for licking the hindpaws. Our results revealed that atypical
antipsychotics have antidepresant, anxiolytic and analgesic effects and can be used in
schizophrenic patients with mood and pain disorders.
(1) Department of Pharmacology - University of Kocaeli - Turkey | (2) Department of PharmacologyUniversity of Sakarya-Turkey
EFFECTS OF QUETIAPINE AND ARIPIPRAZOLE ON MEMORY, DEPRESSION
AND ANXIETY IN MICE, ALTERED GEN EXPRESSION LEVELS IN THE
HIPPOCAMPUS OF MICE
Akar, Furuzan (1) | Gumuslu, Esen (2) | Mutlu, Oguz (1) | Ulak, Guner (1) | Celikyurt, Ipek, K
(1) | Erden, Faruk (1)
Effects of drugs on depression, anxiety and cognition is important in some of the illness such as
alzheimer, dementia and depression comorbiding to schizophrenia and also for enhancing the
life quality of the patients. The aim of this study was to investigate the effects of quetiapine
and aripiprazole on depression, anxiety and memory in naive mice, using the forced swiming
test (FST), elevated plus maze (EPM) and passive avoidance tests. Since the genes involved in
neurite remodeling are among the primary targets of regulation, the effects of chronic
administration of drugs on brain-derived neurotrophic factor (BDNF), cyclic adenosine
monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid
(mRNA) levels in the hippocampus of mice were also determined using quantitative real-time
polymerase chain reaction (RT-PCR).
Mice were treated chronically with quetiapine (5 and 10 mg/kg) and aripiprazole (3 and 6
mg/kg) for 15 days and the drugs were also administered intraperitoneally 60 min before the
tests.
Our study revealed that (1) In the FST test, quetiapine (5 mg/kg; p<=0.05) and aripiprazole (6
mg/kg; p<=0.01) significantly decreased immobility (2) In the EPM test, there was no significant
effect of quetiapine and aripiprazole on %time spent in open arm’s and % open arm entries (3)
In the passive avoidance test, aripiprazole (3 mg/kg; p<=0.05 ) significantly decreased retention
latency while quetiapine had no impairing effect on memory.
Here we demonstrated that chronic administration of quetiapine and aripiprazole had
significant enhancing effect on BDNF expression levels in the hippocampus of mice. Increased
BDNF induced by these antipsychotics was also associated with enhanced expression of CREB.
Our results revealed that both quetiapine and aripiprazole can be effective in schizophrenic
patients with depression although quetiapine had a superior effect since it didn’t disturbed
memory in the passive avoidance test.
(1) Department of Pharmacology - University of Kocaeli - Turkey | (2) Department of GeneticsUniversity of Kocaeli-Turkey
Akar Furuzan | [email protected]
SUPERIOR EFFECT OF QUETIAPINE COMPARED TO ARIPIPRAZOLE AND
ILOPERIDON ON MK-801 INDUCED OLFACTORY MEMORY IMPAIRMENT IN
FEMALE MICE
Mutlu, Oguz (1) | Mutlu, Ahmet (2) | Ulak, Guner (1) | Celikyurt, Ipek, K (1) | Akar, Furuzan
(1) | Erden, Faruk (1) | Kaya, Havva (1)
Cognitive dysfunction is frequently seen in many schizophrenic patients and may be further
aggravated by antipsychotic treatments. While atypical antipsychotics have some beneficial
effects on the cognitive dysfunction in schizophrenia, typical antipsychotics lack the ability to
improve cognitive dysfunction in schizophrenics. It is postulated that insufficient glutamate
neurotransmission is involved in the neuropathophysiology of schizophrenia. In humans, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine and
ketamine, induce schizophrenia-like symptoms including cognitive symptoms. Therefore, NMDA
receptor antagonist-treated animals have been used as models for schizophrenia. A highly
specific non-competitive NMDA receptor antagonist MK-801(dizocilpine) impairs learning and
memory functions that depend on the hippocampus and the amygdala . Quetiapine and
aripiprazole are atypical antipsychotic drugs used frequently in the clinics while ilioperidone is
a newly developed atypical antipsychotic drug. The aim of this study was to investigate the
effects of quetiapine, aripiprazole and ilioperidone on olfactory memory in mice, using the
social transmission of food preference test (STFP); moreover to evaluate the effects of drugs
on MK-801 induced cognitive dysfunction. Female balb-c mice were treated with quetiapine (5
and 10 mg/kg), aripiprazole (3 and 6 mg/kg), ilioperidone (0.5 and 1 mg/kg) or MK-801 (0.1
mg/kg) alone or concurrently before the retention session of STFP test. Our study revealed that
(1) In the STFP test, quetiapine (10 mg/kg; p<=0.05), aripiprazole (3 and 6 mg/kg), ilioperidone
(0.5 and 1 mg/kg) and MK-801 significantly decreased cued/total food eaten (2) Quetiapine (3
mg/kg) significantly increased MK-801 induced decreasement in cued/total food eaten while
aripiprazole and ilioperidone had no effect. Our results revealed that all the drugs investigated
disturbed olfactory memory in naive mice while only quetiapine reversed MK-801 induced
memory impairment in the STFP test.
(1) Department of Pharmacology - University of Kocaeli - Turkey | (2) Department of
Otorhinolaryngology- University of Kocaeli- Turkey
[email protected] | [email protected] | [email protected] | [email protected]
Tuesday 15th September
QUETIAPINE AND ARIPIPRAZOLE UPREGULATE FGF2, SYNAPSIN AND NGF
EXPRESSION IN THE HIPPOCAMPUS OF NAIVE MICE
Mutlu, Oguz (1) | Gumuslu, Esen (2) | Ulak, Guner (1) | Ertan, Merve (2) | Celikyurt, Ipek, K
(1) | Akar, Furuzan (1) | Erden, Faruk (1)
Schizophrenia is a common and serious mental disease in which altered neuroplasticity
contributes to its pathophysiology . Neurotrophins are a large family of dimeric polypeptides
that promote the growth and the differentiation of developing neurons in the central and
peripheral nervous systems. The antipsychotic drugs alter the levels of neurotrophins, which
may contribute to enhanced neurogenesis. Fibroblast growth factor-2 (FGF2) is a trophic factor
widely distributed in the adult brain, whose expression can be modulated by psychoactive drugs.
FGF2 has an important role in many aspects of CNS functioning. It activates CREB and regulates
cell proliferation via phosphorylation of CREB. FGF2 is involved in regulating synaptic plasticity.
Improve memory increase endogenous FGF2, suggesting that increases in FGF2 activity may be
the underlying mechanism of action for memory enhancement. Conditions reducing anxious
behavior increases FGF2 expression in the hippocampus; so FGF-2 is an important modulator of
state anxiety. There is evidence that NGF promotes survival and cellular plasticity. Synapsin
plays an important role in synaptic transmission and neural development. So it plays an
important role in hippocampally based behaviors.
Mice were treated chronically with quetiapine (5 and 10 mg/kg) and aripiprazole (3 and 6
mg/kg) for 15 days and drugs were also administered intraperitoneally 60 min before the tests.
Since the genes involved in neurite remodeling are among the primary targets of regulation,
the effects of chronic administration of quetiapine and aripiprazole on FGF2, synapsin and NGF
levels in the hippocampus of mice were determined using quantitative real-time polymerase
chain reaction (RT-PCR). Administration of the atypical antipsychotic quetiapine and
aripiprazole up-regulated the expression of FGF2, synapsin and NGF and in the mice
hippocampus.
These results suggest that chronic administration of atypical antipsychotics quetiapine and
aripiprazole may promote neuroplasticity via the up-regulation of neutropic factors.
(1) Department of Pharmacology- University of Kocaeli-Turkey | (2) Department of GeneticsUniversity of Kocaeli- Turkey
Email: [email protected] | [email protected] | [email protected] | |
TEMPORAL ERROR DETECTION IN PRE-WEANING RATS
Tallot, Lucille (1) | Skzyba, Karina (2) | Mouly, Anne-Marie (3) | Sullivan, Regina (2) |
Doyere, Valerie (1)
In Pavlovian aversive conditioning, the animal learns the association between a conditioned
stimulus (CS) and an unconditioned stimulus (US) but also that the CS predicts the time of
arrival of the US. In adults, the CS-US time interval is learned within a few trials. After learning,
a memory is consolidated to become stable; however, a reminder of the learning can destabilize
this memory which then induces reconsolidation. After a strong conditioning, reconsolidation
is activated only if the rat detects a difference between the initial learning and the reactivation
trial, like a change in the predictability of the US by modifying the CS-US interval (Diaz-Mataix
et al., 2013). We used reconsolidation as a tool to determine if pre-weaning pups (PN18-20) are
capable of differentiating temporal intervals. Pre-weaning pups have a fully functional
amygdala (essential for aversive conditioning), but immature prefrontal cortex and striatum,
two structures described as being essential in interval timing. We conditioned animals with 10
CS-US associations (with an interval of either 10 or 30s) and presented, 24h later, a reactivation
trial using a CS-US presentation with the same (no-shift) or a different (shift) interval, or a CS
alone. We injected rapamycin (inhibitor of mTOR and blocking agent for reconsolidation)
immediately after the reactivation and measured the freezing to the CS one day later. Preweaning pups (PN18-20) detected the lack of the US or a change in the CS-US interval. As in
adults, reconsolidation was triggered by a CS alone trial (decreased freezing), and no
reconsolidation was induced by a no-temporal shift trial during reactivation (no change in
freezing). However, an increase in freezing to the CS was observed when rapamycin was
injected after a reactivation with a temporal shift. Our results suggest that pre-weaning pups
can detect a temporal error without a mature prefrontal cortex and striatum.
(1) Université Paris-Sud - Orsay - France | (2) Emotional Brain Institute (EBI) - Orangeburg - USA | (3)
Center of Research in Neurosciences of Lyon - France
Tallot Lucille | [email protected]
EEG DINAMICS DIFFERENCES IN BEHAVIORAL STRATEGIES OF YOUNGER
SCHOOLCHILDREN IN RECOGNITION OF AUDIO SIGNAL AND IN A VISUAL
STOP-SIGNAL PARADIGM
Tamozhnikov, Sergey, Sergeevich (1) | Levin, Evgeny, Andreevich (1.4) | Stepanova,
Valentina, Vasil`evna (2) | Savostyanov, Aleksandr, Nikolayevich (1.3.5)
The aim of study was to compare the behavioral responses in younger schoolchildren in
attention tasks and motor control. 56 first graders (mean age 7.5 years) were examined. State
of the attention system was observed by using odd-ball paradigm both monophonic sound and
polyphonic syllables as stimuli and a visual paradigm Stop Signal (SSP) which allow to evaluate
individual features of motor control. In odd-ball paradigm with monophonic stimulation
schoolchildren had three behavioral strategies - regular (reaction after task), chaotic (reaction
is not related with task) and semichaotic (mixed), whereas polyphonic condition differences of
behavior strategies was not found. Individual differences of reactions in conditions odd-ball
significantly correlated with indicators of behavior in the SSP. In the second observation, the
number of children with chaotic and mixed behavioral strategies was decreased from 47 % to
16 % of the total sample. At the polyphonic stimulation, the P300 peak in the frontal cortical
areas was detected after the target signal onset. At the monophonic stimulation, the P300 peak
was not observed in the frontal areas for any of the signals, but was observed in the parietal
regions in response to both types of signals. Intergroup comparison showed that "Regular" group
had the frontal P300 peak to the target stimulus. "Semichaotic" group in polyphonic stimulation
showed a shift of the P300 peak to temporal cortical regions, and in monophonic condition they
had not the P300 peak to the target stimulus. "Chaotic" group in polyphonic stimulation showed
no frontal P300 peak, and in monophonic stimulation they had a negative peak in the left
temporal area (Broca's area). In the SSP, the largest amplitude of alpha-beta desynchronization
was observed in "Regular" group, and the lowest - in "Chaotic" group. This work was supported
by the Russian Science Foundation (RSCF) under Grant № 14-15-00202.
(1) "Scientific Research Institute of Physiology & Basic Medicine" Novosibirsk-Russia
(2) "Novosibirsk Regional Institute for Education Development" Novosibirsk-Russia.
(3) "Tomsk State University" Tomsk-Russia.
(4) "Institute of Circulation Pathology n.a. academician E.N. Meshalkin of Minzdrav of Russia"
Novosibirsk-Russia.
(5) "Novosibirsk State University" Novosibirsk-Russia
Tamozhnikov Sergey Sergeevich | [email protected]
ABUSE POTENTIAL OF ORAL PHENDIMETRAZINE IN COCAINE-DEPENDENT
INDIVIDUALS
Stoops, William, W (1) | Bolin, Barrett, L (1) | Sites, Jeremy (1) | Rush, Craig, R (1)
Aim: Phendimetrazine is a prodrug for the monoamine releaser phenmetrazine, a drug with
known abuse potential. Preclinical studies suggest that phendimetrazine has limited abuse
potential and may have promise as an agonist-like replacement therapy for cocaine dependence.
No clinical studies have evaluated the abuse potential of phendimetrazine. The hypothesis of
this study was that phendimetrazine would have reduced abuse potential relative to damphetamine in cocaine-using humans.
Methods: Nine cocaine-dependent volunteers (N = 9) completed this double-blind, placebocontrolled, within-subjects study. The cardiovascular and subjective effects of oral
phendimetrazine (35, 70, and 105 mg), d-amphetamine (10, 20, and 30 mg) and placebo were
assessed at regular intervals for 6 h after drug administration. Data were analyzed as peak
effect using repeated-measures analysis of variance with Fisher’s least significant difference
post hoc tests to compare between means.
Results: The highest dose of phendimetrazine significantly increased heart rate compared to
placebo, but did not systematically alter blood pressure. d-Amphetamine dose-dependently
increased blood pressure and heart rate. Neither phendimetrazine nor d-amphetamine
significantly increased ratings of positive or negative subjective effects relative to placebo.
Conclusion: These preliminary findings suggest that phendimetrazine and d-amphetamine have
limited abuse potential in cocaine-dependent individuals, a clinically relevant sample that
could receive these medications to help manage cocaine-use disorder. Future studies are
needed to further elucidate the potential utility of phendimetrazine as an agonist-like
replacement therapy for cocaine dependence.
Supported by: Grants R01DA025032 and T32DA035200.
Main Theme: C.17.x. Addiction: Behavioral pharmacology
(1) University of Kentucky - USA
Email: [email protected] | [email protected] | [email protected] | [email protected]
Stoops William W | [email protected]
NICOTINE SELF-ADMINISTRATION INDUCES A REMODELING OF
PERINEURONAL NETS AND THE PATTERN OF ACTIVATION IN
ORBITOFRONTAL CORTEX
Bardo, Michael, Thomas (1) | Vazquez-Sanroman, Dolores, Beatriz (1)
Nicotine is the principle addictive agent delivered via cigarette smoking. Nicotine excites
different types of neurons and modulates synaptic plasticity. Activity of mPFC neurons is highly
modulated by GABAergic interneurons, the majority of which are enveloped by specialized
structures called perineuronal nets (PNNs), which are integral to maintaining many types of
plasticity. This study investigated PNNs in mPFC (prelimbic and infralimbic subregions) and
orbitofrontal cortex (OFC) following intravenous (IV) nicotine self-administration training in rats.
METHODS
Male Sprague-Dawley rats (n=32) were used. After jugular catheter implantation, rats were
tested 21 days for nicotine self-administration (0.03 mg/kg) 1-h daily sessions with an
incrementing FR requirement (FR1 to FR5); a control group received saline infusions only. Rats
were killed 30 min after the last session and brains collected for analyses of c-Fos, parvalbumine
and PNNS.
To address differences in response rates, a 2x2 (drug x lever) ANOVA was conducted. A
significant main effect for drug [F (1, 24)=10.45, p<=0.001] and lever [F(1,24)=82.41,
p<=0.0001] and interaction effect [F (1, 24) = 10.95, p
CONCLUSIONS
The OFC represents one of the neural substrates where nicotine self-administration modifies
cortical neuronal activation and PNN remodeling, which may lead to long-term
neuroadaptations following tobacco use.
supported by: NIH grants P50 DA05312 and R01 DA12964.
(1) Department of Psychology - University of Kentuckyand Center for Drug Abuse Research Translation
(CDART)
Bardo, Michael, Thomas | [email protected]
PERCEPTIONS OF RESEARCH RISK AND UNDUE INFLUENCE IN AN ONLINE
SAMPLE OF COCAINE USERS
Strickland, Justin, C (1) | Stoops, William, Wm (1)
Human behavioral pharmacology research has been guided by the ethical principles of respect
for persons, beneficence and justice. Despite the prominence of these ethical guidelines, few
empirical studies exist that have examined subject perceptions of adherence to these principles.
To address this gap, the present study examined perceptions of research participation in human
behavioral pharmacology research, including the relative risk of research procedures and
possible undue influence related to monetary compensation, using an online sample of cocaine
users. The study was conducted on Amazon.com’s Mechanical Turk (mTurk), a crowdsourcing
website that has recently become a popular alternative to in-person laboratory experiments
for survey-based research. mTurk is highly efficient, cost-effective, and provides sampling of
diverse populations to which researchers may not otherwise have access. Of the 1764 individuals
screened, 138 reported past year cocaine use (7.8%). This sample of cocaine users was
predominantly young (mean = 29.2 years) and male (68.8%). These individuals also reported
approximately 5.1 years of cocaine use (sd = 4.9) and largely indicated intranasal use as the
preferred route of administration (88.4%). Ratings of research risk revealed that most
participants found common research practices in behavioral pharmacology as less than or equal
to the relative risk of everyday life. Receiving experimental medication outside the hospital
was rated as the most risky research activity, but on average was not rated as presenting more
risk than everyday life. Desired compensation for research participation was associated with
the perceived risk of research activities. However, increases in desired compensation for
participation was only observed for research perceived as presenting much more risk than
everyday life. Taken together, these findings indicate that the design and conduct of human
behavioral pharmacology research adheres well to accepted ethical principles.
This work was supported by funds from the Department of Behavioral Science to WWS.
Strickland Justin C | [email protected]
SELF-REFERENTIAL PROCESSING AND ANHEDONIA IN SCHIZOPHRENIA
Jung Suk, Lee (1) | Seon-Koo, Lee (1) | Jae-Jin, Kim (1)
Impairments in the self-referential processing may be associated with anhedonia in patients
with schizophrenia. This study aimed to investigate the neural bases of dysfunctional selfreferential processing and its relationship with anhedonia in patients with schizophrenia
specifically in self-related brain regions of interest (ROIs) including the ventral medial
prefrontal cortex (VMPFC) dorsal medial prefrontal cortex (DMPFC), anterior cingulate cortex
(ACC), posterior cingulate cortex (PCC), precuneus, and insula. Twenty patients with
schizophrenia and 25 healthy controls underwent functional magnetic resonance imaging, while
they rated the extent of association between faces (self, famous or unfamiliar) and words
(positive, negative or neutral). Patients with schizophrenia were more likely to rate self face
as negative than healthy controls. Patients showed significantly increased activities in the ACC
and precuneus ROIs than controls. In addition, the activity in the ACC ROI was positively
correlated with anhedonia in patients with schizophrenia. In conclusions, this study provides
new evidence that disrupted self-referential processing may be a possible cause of anhedonia
in patients with schizophrenia.
(1) National Health Insurance Service Ilsan Hospital - South Korea
Jung Suk Lee | [email protected]
ALCOHOL ADMINISTRATION INCREASES COCAINE CRAVING BUT NOT
COCAINE CUE ATTENTIONAL BIAS
Marks, Katherine, R (1) | Pike, Erika (1) | Stoops, William, W (1) | Rush, Craig, R (1)
Background: Alcohol consumption is a known antecedent to cocaine relapse. Through
associative conditioning, it is hypothesized that alcohol increases incentive motivation for
cocaine and thus the salience of cocaine-related cues, which are important in maintaining drugtaking behavior. Cocaine-using individuals display a robust cocaine cue attentional bias as
measured by fixation time during the visual probe task. The purpose of the present study was
to evaluate the influence of alcohol administration on cocaine cue attentional bias using eyetracking technology to directly measure attentional allocation.
Methods: Twenty current cocaine users completed a double blind, placebo-controlled, withinsubjects study that tested the effect of three doses of alcohol (0.00, 0.325, 0.65 g/kg alcohol)
on cocaine cue attentional bias using the visual probe task with eye-tracking technology. In this
task, cocaine-related and matched neutral images were presented side-by-side. Eye-tracking
technology measured time spent fixating on each image. Cocaine cue attentional bias scores
were calculated as the difference in fixation time between the cocaine-related and matched
neutral images. The participant-rated and physiological effects of alcohol were also assessed.
Results: Participants displayed a robust cocaine cue attentional bias following both placebo and
alcohol administration as measured by fixation time (F(1,19) = 17.9,
p <= 0.05). Alcohol administration did not influence cocaine cue attentional bias,
but dose dependently increased craving for cocaine (F(12,228) = 3.4,
p <= 0.05). Alcohol produced prototypic psychomotor and participant-rated effects.
Conclusions: Alcohol administration increases cocaine craving but not cocaine cue attentional
bias. Alcohol-induced cocaine craving suggests that alcohol increases incentive motivation for
cocaine but not the salience of cocaine-related cues. This research was supported by NIDA
Grants R01 DA025032 and R01 DA025591 [CRR], T32 DA035200 [CRR, KRM], NCATS Grant TL1
TR000115 [KRM], as well as by internal funding from the University of Kentucky [WWS].
Marks Katherine R | [email protected]
HIPPOCAMPAL MONOACYLGLYCEROL LIPASE INHIBITION SELECTIVELY
IMPAIRS MEMORY RETRIEVAL OF STRESSFUL EXPERIENCES
Morena, Maria (1,2) | De Castro, Valentina (1) | Gray, J Megan (2) | Palmery, Maura (1) |
Trezza, Viviana (3) | Roozendaal, Benno (4) | Hill, Matthew N (2) | Campolongo, Patrizia (1)
There is now a growing body of literature that indicates that cannabinoid drugs can induce dual
effects on cognitive and emotional behavior depending on the aversiveness of the
environmental context and the level of emotional arousal1,2,3. It has been shown that variation
in environmental aversiveness differentially influences spatial memory processes in rats4,5.
Here, we investigated whether the hippocampal endocannabinoid system differentially
modulates retrieval of spatial memory of rats trained at two different stress levels. Male adult
Sprague Dawley rats were trained in a Morris water maze task at two different water
temperatures (19°C and 25°C)5. Sixty minutes before the retrieval trial the cannabinoid agonist
WIN55,212-2, the 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor JZL184 and the anandamide
(AEA) hydrolysis inhibitor URB597 were bilaterally infused into the hippocampus. We found that
treatment with WIN55,212-2 or JZL184, but not URB597, impaired memory retrieval only in rats
trained under the high stress condition (19°C). Interestingly, at the time of memory retrieval,
we found that, non-treated animals trained at the higher stress condition had increased
hippocampal 2-AG levels, but not AEA, and a decrease in the affinity of the main 2-AG
degradative enzyme for its substrate. Taken together, these findings indicate that the
hippocampal endocannabinoid 2-AG plays a key role in the regulation of spatial memory
retrieval of stressful experiences, fine-tuning hippocampal neuronal activity and neurocircuitry
function involved in the retrieval of stressful information.
References:
Haller et al. (2009) Psychopharmacology (Berl). 204: 607-616.
Morena and Campolongo. (2014) Neurobiol Learn Mem. 112: 30-43.
Campolongo et al. (2013) Neuropsychopharmacology. 38: 1276-1286.
Akirav et al. (2004) Learn. Mem. 11: 188-195.
Salehi et al. (2010) Learn. Mem. 17: 522-530.
Acknowledgements:
This study was supported by grants from Human Frontier Science Program (HFSPRGY0077/2012)
and from FIRB Futuro in Ricerca to PC, operating funds from the Canadian Institutes of Health
Research to MNH and by fundings from the Italian Society of Pharmacology (SIF) to MM.
(1) Sapienza University of Rome - Italy | (1) Sapienza University of Rome - Italy | (2) University of
Calgary - Canada | (1) Sapienza University of Rome - Italy | (3) University Roma Tre - Italy | (4)
Radboud University - The Netherlands
[email protected] | [email protected] | [email protected] |
[email protected] | [email protected]
Morena Maria | [email protected]
MGLU5 RECEPTORS IN THE EXTINCTION OF COCAINE-ASSOCIATED CUES
Perry, Christina, J (1) | Reed, Felicia (2) | Zbukvic, Isabel, C (1) | Kim, Jee Hyun (1) |
Lawrence, Andrew, J (1)
Drug-associated cues motivate drug-seeking, and cue extinction forms the basis of behavioural
therapies targeting substance abuse. Here we examined whether Pavlovian extinction of a drugassociated stimulus (CS) would decrease the ability of that CS to reinstate an instrumental drugseeking response, and the role of the mGlu5 receptor in CS extinction. In Experiment 1, all rats
were trained to lever press for intravenous administration of cocaine (0.3mg/kg/infusion),
paired with a light CS. The lever pressing was extinguished in the absence of the CS. CS
extinction occurred on the day following last day of lever extinction. Half of the rats were
placed in the operant chambers and given 120 non-reinforced presentations of the CS, but with
the levers retracted. The remaining rats were handled but received no further training. All rats
received an intraperitoneal injection of either an mGlu5 negative allosteric modulator (MTEP)
(2mg/kg) or vehicle 20 minutes prior to this session. Cue-induced reinstatement was tested the
following day by re-pairing the lever with the CS in the absence of any further primary
reinforcement. Rats gave fewer drug-seeking responses following CS extinction than following
handling alone (p <= 0.05). This effect was attenuated by MTEP (p <= 0.05). Experiment 2
followed the same protocol as Experiment 1, except that a positive allosteric modulator CDPPB
(60mg/kg) or vehicle was administered i.p. 20 minutes prior to CS extinction. At reinstatement
(drug free), cue-elicited cocaine seeking was lower for the animals that had previously been
administered CDPPB, regardless of extinction condition (p <= 0.05). This study shows that
Pavlovian CS-drug associations are important for driving instrumental drug-seeking behaviour
during reinstatement; and that mGlu 5 signalling is necessary and sufficient for extinction of
CS-drug associations.
(1) Florey Institute of Neuroscience and Mental Health - University of Melbourne - Australia
Perry Christina J | [email protected]
CEREBELLAR SIGNATURES OF COCAINE-INDUCED PREFERENCE
CONDITIONING
Carbo-Gas Maria (1) | Gil-Miravet, Isis (1) | Carulli, Daniela (1) | Sanchis-Segura, Carla (1) |
Miquel, Marta (1)
Several memory processes underlie motivational trigger of drug-seeking and drug-taking
behaviour. One of them is the acquisition of preference memories for drug-related cues. It is
now well accepted that addictive drugs produce long-lasting molecular and structural plasticity
alterations in cortico-striatal-limbic circuits. However, and despite the fact that several data
have supported the involvement of the cerebellum in the functional alterations observed after
prolonged cocaine use, this brain region has been traditionally ignored from the circuitry
affected by addictive drugs. Recently, we have shown that preference for the odour associated
with cocaine was directly correlated with cFOS expression in cells at the apex of the granule
cell layer of the cerebellar vermis. In the present study, we further investigate the cerebellar
signatures of cocaine-induced conditioned preference. We evaluated several structural plastic
modifications together with cFos expression in the cerebellar cortex of mice trained to acquire
preference towards cues associated with cocaine. Using wisteria floribunda agglutinin, we
estimated the expression of perineuronal nets (extracellular matrix structures restricting
plasticity) around Golgi inhibitory interneurons of the granule cell layer, as well as around
neurons of the deep cerebellar nuclei. In addition, we examined alterations in the dendritic
arborization of Purkinje cells.
A discriminant analysis considering all the variables evaluated yielded two very specific
cerebellar hallmarks of cocaine-induced conditioned preference: an increase in cFos levels in
the granular cells at the apex of the cerebellar cortex and a stronger expression of perineuronal
nets surrounding Golgi cells of the same region. Both cerebellar signatures were not seen if
mice did not develop a preference for the cocaine-related cue. The other parameters did not
show any relationship with preference conditioning but only with the global pharmacological
effect of cocaine.
(1) Psychobiology - Univ. Jaume I - Castellón De La Plana - Spain
[email protected]
Carbo-Gas Maria | [email protected]
A TOUCHSCREEN ASSESSMENT OF THE TGTAUR406W MOUSE MODEL OF
FRONTOTEMPORAL DEMENTIA REVEALS AGE-DEPENDENT REWARDRELATED BEHAVIOURAL DISTURBANCES
Phillips, Benjamin (1) | Heath, Christopher, J (1) | Bussey, Timothy, J (1) | Saksida, Lisa, M
(1)
Though typically associated with debilitating memory impairments, dementia sufferers also
often exhibit profound behavioral and psychological symptoms (BPSD), including apathy,
irritability, anergia, behavioural disinhibition and hallucinations. Though frequent in
presentation and highly deleterious, little is known of the underlying neurobiological
mechanisms and there are currently no accepted BPSD therapeutics. To facilitate improved
understanding of the underlying maladaptive psychological and neural mechanisms and
subsequently screen putative therapeutics, it is therefore necessary to identify an appropriate
animal model.
The TgTauR406W mouse model of frontotemporal dementia is known to exhibit a depressivelike phenotype in addition to profound memory disturbances. To determine if this animal also
exhibits evidence of reduced motivation, consistent with apathy-like behaviour, we
longitudinally assessed a cohort of these mice on a touchscreen version of the progressive ratio
test of motivation. This revealed age-dependent alterations in reward-related motivated
behavior.
Specifically, young TgR406W animals earned fewer reinforcers than wild-type littermates,
consistent with reduced motivation, and this pattern then reversed with extended ageing. We
hypothesized that this subsequent paradoxical facilitation is mediated by executive
disinhibition resulting from frontal cortex specific degeneration. To determine if executive
disinhibition had occurred, we assessed the aged mice on the 3-choice serial reaction time test
of executive function.
Taken together, the alterations in motivated and reward-relaDepartment of Psychology and
MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute - University of Cambridge
- UKted behaviours indicate that the TgTauR406W mouse may prove a strong candidate for
modeling diverse aspects of BPSD.
(1) Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience
Institute - University of Cambridge - UK
Phillips Benjamin | [email protected]
SEPARATE AND COMBINED EFFECTS OF NALTREXONE AND EXTENDEDRELEASE ALPRAZOLAM ON THE REINFORCING, SUBJECT-RATED, AND
PHYSIOLOGICAL EFFECTS OF METHAMPHETAMINE
Pike, Erika (1) | Marks, Katherine, R (1) | Lile, Joshua, A (1) | Stoops, William, W (1) |
Glaser, Paul, E A (1) | Hays, Lon, R (1) | Rush, Craig, R (1)
Opioid antagonists (e.g., naltrexone) and positive modulators of GABA-A receptors (e.g.,
alprazolam) modestly attenuate the abuse-related effects of stimulants. Side effects preclude
the use of higher doses to achieve greater efficacy. Combining naltrexone and extended-release
alprazolam (alprazolam XR) might maximize efficacy while avoiding the untoward effects of
higher doses of the constituent compounds.
This study tested the influence of naltrexone and alprazolam XR on the reinforcing, subjectrated, and physiological effects of methamphetamine. We hypothesized that maintenance on
the combination of naltrexone and alprazolam XR would be well tolerated, decrease selfadministration, and reduce the “positive” subject-rated drug-effects of methamphetamine to
a greater extent than the constituent drugs alone.
Eight non-treatment-seeking, stimulant-users were maintained on placebo, naltrexone (50 mg),
alprazolam XR (1 mg), and a combination of naltrexone and alprazolam. Participants completed
three sessions under each maintenance condition during which they first sampled one of three
doses of intranasal methamphetamine (0, 10, and 30 mg) and completed physiological and
subjective effects measures. Participants then had the opportunity to respond on a progressive
ratio task to earn all, some, or none of the sampled methamphetamine dose.
Methamphetamine produced prototypical physiological and stimulant-like “positive” subjective
effects (e.g., Like Drug). Naltrexone maintenance decreased self-administration of 10 mg
methamphetamine compared to all other maintenance conditions. Naltrexone and alprazolam
XR alone each significantly attenuated some of the subjective effects of methamphetamine.
The combination did not attenuate methamphetamine self-administration or subjective effects.
Overall, the results support the continued evaluation of naltrexone for methamphetamine
dependence, with particular attention to the identification of other drugs that might enhance
its ability to reduce drug-taking behavior.
This research was supported by NIDA Grants R01 DA025591 (CRR), T32 DA035200 (CRR and KRM),
K02 DA031766 (JAL) and CTSA Grants UL1 TR000117 and UL1 TR000115 (KRM).
Pike Erika | [email protected]
THE IMPACT OF SOCIAL CONTEXT ON CIGARETTE SELF-ADMINISTRATION
IN NON-DEPENDENT SMOKERS
Schlagintweit, Hera, E (1) | Reymarova, Ekaterina (1) | Barrett, Sean, P (1)
Objective. Tobacco use in non-dependent smokers (i.e. chippers) is thought to be largely
determined by situational factors including social context. However, little empirical research
has examined how different social contexts impact chippers’ smoking behaviour. Methods.
Twenty eight (16 male) chippers completed two laboratory sessions where they were offered
an opportunity to self-administer puffs of their preferred tobacco brand in a progressive ratio
task. During an individual session, participants self-administered cigarettes alone, and during a
paired session participants self-administered cigarettes with a co-participant who was also
smoking. Results. The strongest predictors for number of self-administered puffs and breakpoint
during the paired session were co-participants’ number of puffs and breakpoint respectively (p
values<=0.001), followed by puffs taken and breakpoint during the individual session (p
values<=0.01). Current smoking frequency (cigarettes/week) did not significantly predict puffs
taken or breakpoint during the paired session. Latency to cigarette self-administration during
the paired session was positively correlated with co-participants’ latency (p=0.044) but not
latency during the individual session or cigarettes/week (p values>0.10). Conclusions. Findings
suggest that social context exerts an important influence on the quantity of chippers’ smoking
behaviour, such that chippers come to match their smoking behaviour to that of other smokers
in their proximate environment.
Source of funding: Funding for this study was provided by a grant from the Natural Science and
Engineering Council of Canada (NSERC)
(1) Dalhousie University - Canada
Schlagintweit Hera E | [email protected]
CHRONIC EFFECTS OF THE 'BIASED' 5-HT1A RECEPTOR AGONISTS F15599
AND F13714 ON OBJECT PATTERN SEPARATION PERFORMANCE AND
HIPPOCAMPAL PLASTICITY
van Hagen, Britt, T.J. (1) | van Goethem, Nick, P. (1) | Schreiber, Rudy (2) | NewmanTancredi, Adrian (3) | Varney, Mark (3) | Prickaerts, Jos (1)
Pattern separation, the formation of distinct representations out of similar inputs, is an
important hippocampal process implicated in memory formation. Impairments in pattern
separation could underlie cognitive symtoms of disorders like PTSD and schizophrenia. Our
previous research showed that acute treatment with the ‘biased’ 5-HT1A agonist F15599, which
preferentially activates postsynaptic cortical heteroreceptors, improved rat performance in a
spatial object pattern separation (OPS) task. In contrast, F13714, which preferentially activates
raphe-located autoreceptors, impaired performance in this task. Here we investigated the
effects of chronic treatment with F15599 and F13714 on spatial OPS performance in rats. We
hypothesized that, through desensitization of raphe-located autoreceptors by F13714, OPS
performance impairment would ameliorate due to increased activation of postsynaptic
receptors. Daily core temperature measurents were included as a readout of postsynaptic 5HT1AR activation. Rats were treated daily with F15599, F13714 or vehicle. OPS performance
was assessed after treatment day 1, 8 and 14. The OPS impairment after acute treatment of
F13714 was replicated and subsequently a gradual increase of performance was found,
resembling vehicle treatment on day 15. Body temperature dropped by 1 degree celcius from
treatment day 4 onwards. F15599 showed an enhancement in OPS performance compared to
vehicle acutely, and this was maintained through day 15. These results imply possible
desensitization of 5-HT1A autoreceptors by F13714, leading to stimulation of
postsynaptic 5-HT1ARs which could explain the drop in temperature. Currently, hippocampal
measurements of plasticity and neurogenesis are being performed. We hypothesize an increase
in plasticity and/or newborn neurons to underlie the increase in OPS performance. Furthermore,
immunohistochemical studies are being performed to asses the number of 5-HT1ARs in the
hippocampus and raphe nucleus.
(1) Department of Psychiatry and Neuropsychology - School for Mental Health and Neuroscience Maastricht University - The Netherlands | (2) Suadeo Drug Discovery Consulting, Charlestown, MA,
USA | (3) Neurolixis, Dana Point, CA, USA
Email: [email protected] | [email protected] |
[email protected]
van Hagen Britt T.J. | [email protected]
EPIGENETIC REGULATION OF NOCICEPTIN/ORPHANIN FQ AND
CORTICOTROPIN-RELEASING FACTOR SYSTEM GENES IN FRUSTRATION
STRESS-INDUCED BINGE-LIKE PALATABLE FOOD CONSUMPTION
Giusepponi, Maria Elena (1) | Micioni Di Bonaventura, Maria Vittoria (1) | Pucci, Mariangela
(2) | Romano, Adele (3) | Maccarrone, Mauro (4) | Ciccocioppo, Roberto (1) | D'Addario,
Claudio (2) | Cifani, Carlo (1)
Evidence suggests that binge eating may be caused by a unique interaction between dieting
and stress. We developed a binge-eating model in which female rats with a history of
intermittent food restriction show binge-like palatable food consumption after 15 min exposure
to the sight of the palatable food (frustration stress). Aim of the present study was to
investigate the regulation of the stress neurohormone corticotropin releasing factor (CRF)
system and of the nociceptin/orphanin FQ (N/OFQ) system genes in selective rat brain regions,
using our animal model. Food restriction by itself might be responsible in the hypothalamus for
the downregulation on mRNA levels of CRF-1 receptor (CRF-1R), N/OFQ as well as its receptor
NOP. For the latter, this alteration might be due to selective histone modification changes.
Instead, CRF gene appears to be upregulated in the hypothalamus and in the ventral tegmental
area only when rats are food restricted and exposed to frustration stress and, of relevance,
these changes appear to be due to a reduction in DNA methylation at gene promoters. Moreover,
CRF-1R mRNA resulted also to be differentially regulated in these two brain regions. Our data
add information on altered N/OFQ and CRF signalling in food restriction and under stressful
conditions, and provide insight on the use of this model of binge eating for the study of
epigenetic modifications in controlled genetic and environmental backgrounds.
ACKNOWLEDGMENTS: The work was supported by the Italian Ministry of University and Research
under grant FIRB-RBFR12DELS to CC and CDA. The authors declare no competing financial
interests.
(1) University of Camerino - Italy | (2) University of Teramo - Italy | (3) Sapienza University of Rome Italy | (4) Campus Bio Medico - Italy
Giusepponi Maria Elena | [email protected]
REGULATION OF HYPOTHALAMIC NEUROPEPTIDES GENE EXPRESSION IN
DIET INDUCED OBESITY RESISTANT RATS: POSSIBLE TARGETS FOR
OBESITY PREDICTION?
Cifani, Carlo (1) | Micioni Di Bonaventura, Maria Vittoria (1) | Pucci, Mariangela (2) |
Giusepponi, Maria Elena (1) | Romano, Adele (3) | Di Francesco, Andrea (2) | Maccarrone,
Mauro (4) | D'Addario, Claudio (2)
Several factors play a role in obesity (i.e. behavior, environment, and genetics) and epigenetic
regulation of gene expression has emerged as a potential contributor in the susceptibility and
development of obesity.
To investigate the individual sensitivity to weight gain/resistance, we here studied gene
transcription regulation of several hypothalamic neuropeptides involved in the control of energy
balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when
fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure.
After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a
selective down-regulation of the orexygenic neuropeptide Y (NPY) and peroxisome proliferatoractivated receptor gamma (PPAR-γ) genes. No changes were observed in the expression of the
agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After longterm high fat diet exposure (21 weeks), NPY and PPAR-γ, as well as most of the genes under
study, resulted not be different between DIO and DR, whereas a lower expression of the
anorexigenic pro-opiomelanocortin (POMC) gene was observed in DIO rats when compared to
DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated
with gene promoters DNA methylation.
Our findings suggest that selective alterations in hypothalamic peptide genes regulation could
contribute to the development of overweight in rats and that environmental factor, as in this
animal model, might be partially responsible of these changes via epigenetic mechanism.
ACKNOWLEDGMENTS: The work was supported by the Italian Ministry of University and Research
under grants FIRB-RBFR12DELS to CC and CDA and PRIN-2012JTX3KL to CC. The authors declare
no competing financial interests.
(1) University of Camerino - Italy
(2) University of Teramo – Italy
(3) Sapienza University of Roma - Italy
(4) Campus Bio Medico - Italy
Cifani Carlo | [email protected]
BASOLATERAL AMYGDALA NICOTINIC ACETYLCHOLINE RECEPTORS
MEDIATES ACUTE STRESS-INDUCED POTENTIATEN OF NICOTINE REWARD
IN RATS
Javadi, Parastoo (1) | Rezayof, Ameneh (1)
Stress is likely to affect nicotine abuse, which may be under significant regulatory control by
hypothalamic-pituitary-adrenal (HPA) axis. The basolateral nucleus of amygdala (BLA) which
has cholinergic projections from the basal forebrain, participates in stress- and reward-related
behaviors through its connections to the prefrontal cortex and the nucleus accumbens,
respectively. In the present study, we examined: 1) the effect of acute stress on nicotine
induced-reward using an unbiased conditioned place preference (CPP) procedure; 2) the
involvement of nicotinic acetylcholine receptors (nAChRs) in the BLA under this effect. In these
experiments, adult male Wistar rats weighting 200-220 g at the time of surgery were used. All
animals were bilaterally cannulated in the BLA by stereotaxic instrument, and were allowed to
recover 1-week before training. After recovery period, the animals were exposed to a 30 min
acute elevated platform stress and immediately after were introduced to the CPP apparatus.
Mecamylamine, as a nACh receptor antagonist, was microinjected into the BLA, 5 min before
the stress exposure. Using a 3-day schedule of conditioning, it was found that treatments with
subcutaneous (s.c.) injections of 0.2 mg/kg of nicotine induced a CPP for the drug-associated
place. Acute stress exposure potentiated the response of an ineffective dose of nicotine (0.1
mg/kg) in the CPP apparatus and induced a significant rewarding effect of nicotine. Intra-BLA
microinjection of different doses of mecamylamine (1-4 µg/rat) significantly increased the
acute stress-induced potentiation of nicotine-induced CPP. It is important to note that intraBLA microinjection of mecamylamine alone had no effect on the CPP acquisition. Considering
that the inhibition of nAChRs in the BLA enhanced the potentiative effect of stress on nicotine
response in the CPP apparatus, it can be concluded that the BLA cholinergic system via nAChRs
may be involved in acute stress-induced potentiation of nicotine reward.
(1) University of Tehran Iran
Javadi Parastoo | [email protected]
BRAIN HISTAMINE IS ESSENTIAL FOR SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRI) BEHAVIOURAL AND NEUROCHEMICAL EFFECTS
Provensi, Gustavo (1) | Munari, Leonardo (2) | Passani, Beatrice (1) | Galeotti, Nicoletta (1)
| Cassano, Tommaso (3) | Corradetti, Renato (1) | Blandina, Patrizio (1)
The neurobiological changes underlying depression resistant to treatments remain poorly
understood. The failure to respond to selective serotonin reuptake inhibitors (SSRIs) may result
from abnormalities of neurotransmitter systems that excite serotonergic neurons, such as
histamine. To test this hypothesis we used behavioral (Tail Suspension Test - TST, 8-OH-DPATinduced hypothermia) and neurochemical (in-vivo microdialysis, Western Blot analysis)
approaches. Mice unable to synthesize histamine, due to either targeted disruption of histidine
decarboxylase gene (HDC-KO) or to injection of alpha-fluoromethylhistidine (α-FMHis), an
irreversible inhibitor of this enzyme were treated with different classes of antidepressants and
tested in the TST. The noradrenaline reuptake inhibitor reboxetine (5-20 mg/kg, ip) or the
tricyclic imipramine (10 mg/kg, ip) reduced immobility in both WT and HDC-KO mice.
Conversely, HDC-KO mice as well as α-FMHis-treated CD1 mice failed to respond to acute and
sub-chronic injections of selective serotonin reuptake inhibitors citalopram (10 mg/kg, ip) or
paroxetine (10 mg/kg, ip). In in-vivo microdialysis experiments citalopram increased
significantly histamine extraneuronal levels in the cortex of freely-moving mice, and
methysergide, a 5-HT1/5-HT2 receptor antagonist abolished this effect, thus suggesting the
involvement of endogenous serotonin. Serotonergic transmission appeared intact in HDC-KO
mice, as citalopram increased significantly and selectively hippocampal 5-HT release, as
measured by microdialysis, and attenuated 8-OH-DPAT-elicited hypothermia. Noteworthy,
administration of citalopram was accompanied by increased cAMP response element-binding
protein (CREB) phosphorylation in the hippocampus of WT but not of HDC-KO mice.
Intracerebroventricular infusion of 8-Br-cAMP (an activator of cyclic AMP-dependent protein
kinase - PKA) increased hippocampal CREB phosphorylation and reduced significantly immobility
time in both genotypes. Our results demonstrate that SSRIs selectively require the integrity of
the brain histamine system to exert their behavioral and neurochemical responses.
Funding: This work was supported by PRIN Grant 2009 2009ESX7T3-003 (Italy), Compagnia di
San Paolo (Italy), CNPq 400289/2012-1 (Brazil).
(1) University of Florence - Italy | (2) Ichan School of Medicine at Mount Sinai - USA | (3) University
of Foggia - Italy
[email protected]
Provensi Gustavo | [email protected]
VULNERABILITY TO SCHIZOPHRENIA-LIKE SYMPTOMS IN HIGH
COMPULSIVE DRINKER RATS SELECTED BY SCHEDULE-INDUCED
POLYDIPSIA
Mora, Santiago (1) | Navarro, Silvia (1) | Colomina, M Teresa (2) (3) | Sanchez-Santed,
Fernando (1) | Alvarez, Roberto (1) | Flores, Pilar (1) | Moreno, Margarita (1)
Psychogenic polydipsia, compulsive non-regulatory fluid consumption, is present in 6-20% of
psychiatric patients with disorders related to compulsivity symptoms, such as OCD, ADHD and
schizophrenia. In the present study, we investigated the relation between schizophrenia-like
symptoms and biomarkers with a compulsive drinking behaviour phenotype in rats. Rats
selected for low (LD) versus high drinking (HD) behaviour on schedule-induced polydipsia (SIP),
were tested in a Latent Inhibition task, using tone and electrical foot shock; and in a Spatial
Reversal Learning task. We also analysed the myelin basic protein in different brain areas of
HD and LD rats. The HD rats, characterized by a compulsive drinking behaviour on SIP, had a
decreased latent inhibition effect, showed by an attenuated response to the inhibitory effect
of tone pre-exposure, compared to the LD group. The HD rats demonstrate behavioural
inflexibility on the Spatial Reversal Learning task, showed by the increased trials to reach the
criterion, incorrect responses and a significant number of perseverative errors during the
reversal phase, compared to LD rats. However, there were no differences in the number of
learning errors between HD and LD rats. Moreover, HD rats showed less myelination in the
centre of the corpus callosum, striatum and amygdala compared to LD rats. These findings
strengths the validity of HD rats selected by SIP as a possible phenotype of compulsive
neuropsychiatric disorders, evidenced by the existence of other symptoms and biological
markers related to schizophrenia and OCD: thus, reduced latent inhibition effect, behavioural
inflexibility and reduced brain myelination. Future studies could contribute to elucidate the
mechanisms underlying the compulsive phenotype of HD rats and its relation with a vulnerability
to schizophrenia.
Stydy funded by a grant from the Ministerio Economía y Competitividad, Spanish Government
(PSI2012-31660).
(1) Department of Psychology - University of Almería - Campus de Excelencia Internacional
Agroalimentario CeiA3 - Almeria - Spain | (2) Department of Psychology and Research Center for
Behavior Assessment (CRAMC) - Universitat Rovira i Virgili – Tarragon | (3) Research in Neurobehavior
and Health (NEUROLAB), Universitat Rovira i Virgili, Tarragona, Spain
Mora Santiago | [email protected]
THE NEUROPROTECTIVE EFFECT OF CARBAMYLATED ERYTHROPOIETIN
DERIVATES ON MODEL BILATERAL PHOTOCHEMICAL THROMBOSIS OF
PREFRONTAL CORTEX IN RATS
Shakova, Fatima, M (1) | Kalinina, Tatyana, I (2) | Romanova, Galina, A
The aim of work was to examine behavioural disturbances and morphological distructions in the
brain cortex of rats after bilateral photochemically induced thrombosis of the prefrontal cortex
and to study the effect of carbamylated erythropoietin (CEPO) and EPO fusion protein
containing TR domain from glycoprotein MUC1 (CEPO-TR), and EPO fusion protein with modified
Fc fragments of IgG1(CEPO-Fc).
Methods: Bilateral focal ischemic damage of the prefrontal cortex (areas Frl and Fr2) was
induced by the method of photochemical thrombosis in rats. After passive avoidance training
and testing rats were treated, respectively, with following regimens: saline, CEPO (25 μg/kg),
CEPO-TR (25 μg/kg); CEPO-Fc (25 μg/kg). The substance was administrated intranasally in 1h
after operation. Neurological deficit and infarct volume were assessed at 4 and 7 days ,
respectively, after operation. Functional state of CNS was determined by conditioned passive
avoidance response (PA), i.e. by the latency of transition from light compartment to dark
compartment (in sec). Morphometric measurements of the areas and volumes of the ischemic
focus on serial slices were carried out on animal brain fixed by plunging into formalin-ethanolacetic acid mixture. The data were statistically processed using Statistica 6.0 software.
Summary of results: After bilateral photothrombosis of the prefrontal cortex and injection of
saline, the latency period of entry into the dark compartment decreased from 300 to 72 sec.
Treatment of rats with CEPO, CEPO-TR, and CEPO-Fc after operation promote restoration of
PA to latency 169, 182, 248 sec, respectively, on day 4. Ischemic damage volume in animals
with CEPO, CEPO-TR and CEPO-Fc on 7th day after operation was 21,8±1,9 (P<=0,15), 15,0±1,8
(P<=0,05), 14,3±2,5 (P<=0,05) against 28,9±2,2mm3 with control injection of
saline.
Conclusion: Our data on model photochemical thrombosis of prefrontal
cortex in rats confirm neuroprotective effect of new carbamylated erythropoietin derivates.
(1) Institute of General Pathology and Pathophysiology of Russian Academia of Science | (2) State
Research Institute of Genetics and Selection of Industrial Microorganisms GosNIIGenetika
Shakova Fatima M. | [email protected]
EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION ON THE
RIGHT MOTOR CORTEX: DIFFERENCES CONCERNING PREVIOUS MUSICAL
TRAINING
Sánchez-Kuhn, Ana (1) | Pérez Fernández, Cristian | Moreno, Margarita (1) | Flores, Pilar (1)
| Sánchez-Santed, Fernando (1)
Anodal -tDCS- transcranial Direct Current Stimulation is a technique that stimulates specific
brain areas producing an increase of its activity: anodal stimulation with low electricity current
has shown to depolarize neurons; while catodal stimulation produces the polarization of the
neurons and a decrease of its activity. Previous studies show high effects of tDCS on the
improvement of cognitive and motor capacities and on the reduction of symptoms of diverse
psychopathologies. Therefore, the aim of the present study is to investigate the online and
offline effects of tDCS, the maintenance of these effects in the long term and the influence of
the previous training of the stimulated area. In the present investigation we study if tDCS
improves motor learning by the stimulation of the right Motor Cortex area (M1). For this
objective, 20 healthy right-handed participants were trained on the Sequence Tapping task SEQTAP- with their left hand. 10 out of 20 participants received 2mA stimulation during 20
minutes / 3 sessions while performing the test. Their Skill Index -SI- was registered before,
during (online), 20 minutes after (offline) and one week later. The results show maintenance
in the long term of the learned motor task in the stimulated participants, while the control
group shows a decrease in their performance. These results got also influenced by the previous
musical training of the participants. These results point up the beneficial effects that anodaltDCS over M1 have on motor learning and underline the great potential of this technique in
neurorehabilitation.
This study was granted by Ministerio de Ciencia e Innovación, Spain (PSI2012-31660) (PSI201455785-C2-1-R) and FEDER EU funds.
(1) University of Almería
[email protected]
Sánchez-Kuhn Ana | [email protected]
STRAIN DEPENDENT EFFECTS OF TRYPTOPHAN DEPLETION DIET ON
COMPULSIVE DRINKING BEHAVIOR AND ASSOCIATED NEUROMECHANISMS
Merchán, Ana (1) | Navarro, Silvia (1) | Campa, L (2) | Suñol, Cristina (2) | Klein, Anders |
Aznar, Susana | Moreno, Margarita | Flores, Pilar
Compulsive behaviour, present in different psychiatric disorders such as OCD, schizophrenia
and drug abuse, is associated with altered levels of monoamines particularly serotonin (5hydroxytryptamine) and its receptor system. The present study investigated whether 5-HT
manipulation, through tryptophan (TRP) depletion diet in Wistar and Lister Hooded rats,
modulates compulsive drinking in Schedule-induced Polydipsia (SIP) and locomotor activity in
the Open-field test. The levels of dopamine, noradrenaline, serotonin and its metabolite were
evaluated, as well as the 5-HT2A and 5-HT1A receptor binding, in different brain regions.
Wistar rats were selected as high (HD) or low (LD) drinkers according to their SIP behaviour,
but Lister hooded rats did not show SIP acquisition. Both strains were fed for 14 days with either
TRP-free diet (T-) or TRP-supplemented diet (T+). TRP depletion diet effectively reduced 5-HT
levels in prefrontal cortex, amygdala and hippocampus in both strains of rats.
TRP depleted HD Wistar rats were more sensitive to 5-HT manipulation showing higher levels
of licks on SIP than non-depleted HD Wistar rats, while LD Wistar and Lister Hooded rats did not
show differences on SIP. In contrast, TRP depletion diet increased locomotor activity in Lister
Hooded rat compared to non-depleted, but no differences were found in Wistar rats. 5-HT2A
receptor binding in the striatum was significantly reduced in TRP depleted HD Wistar rats, while
5-HT1A receptor binding in the PFC was decreased in TRP depleted Lister Hooded rats. The 5HT2A receptor reductions in striatum may be one of the possible mechanisms for increased
compulsive drinking behaviour in vulnerable populations.
These results suggest that alterations of the 5-HT2A serotonergic receptor subtype could be
underlying the compulsive behaviour in different psychiatric disorders.
 
This study was funded by a grant from the Ministerio Economía y Competitividad, Spanish
Government (PSI2012-31660).
(1) University of Almería - Spain | (2) CSIC-IDIBAPS - Barcelona - Spain
Merchán Ana | [email protected]
AN INVESTIGATION OF SOME SOURCES OF VARIATION WITH THE
ANTIDEPRESSANT DESIPRAMINE IN THE RAT FORCED SWIM TEST
Bannerton, Karen (1) | Cronin, Ann (1) | Kleefeld, Silke (1) | Kelly, John, P (1)
The forced swim test (FST) is the most widely used test for evaluating antidepressant efficacy
in rodents. However, the experimental parameters differ markedly between laboratories, often
making comparisons between laboratories challenging. Contributors to variation include animal
age, housing and the antidepressant dosing regime employed. Thus, the aim of this series of
studies was to examine these parameters using the standard antidepressant desipramine (DMI)
in the FST.
Male Sprague-Dawley rats were used. Three experiments were conducted. The first assessed
age, using young (12 weeks old), older (7 months old) and old (16 months old) adult rats. The
second assessed bedding type (sawdust or paper) and/or environmental enrichment. The final
experiment compared subacute and chronic DMI administration prior to the FST. Parametric
data were analysed using either One-Way or Two-Way ANOVA, followed where appropriate by
a post hoc SNK or Tukey test. Non-parametric data were analysed using a Kruskal-Wallis,
followed where appropriate by a post hoc Mann-Whitney U test; p<0.05 was deemed
statistically significant.
There was a significant reduction in immobility and concomitant increase in climbing following
DMI treatment in young, but not in the older or old groups, although in this latter group there
was a trend towards a significant reduction. DMI decreased immobility in all housing
environments, except sawdust bedding with enrichment. DMI increased climbing in the sawdust
bedding alone and the paper bedding with enrichment. Both subacute and chronic DMI
significantly reduced immobility and increased climbing behaviour.
These results demonstrate that antidepressant effects of DMI are profoundly affected by age,
while the rats’ environmental parameters also affect DMI-induced behaviours, in the FST.
Subacute and chronic DMI produced similar effects. This emphasises the need for
standardization of important experimental parameters when utilising the FST, in order for valid
comparisons to be made between laboratories in the search for novel antidepressants.
(1) Discipline of Pharmacology and Therapeutics NUI Galway – Ireland
Bannerton, Karen | [email protected]
THE NUCLEAR RECEPTOR TLX REGULATES MOTOR, COGNITIVE AND
ANXIETY-RELATED BEHAVIOURS DURING ADOLESCENCE AND ADULTHOOD
O'Leary, James, D (1) | Kozareva, Danka, A (1) | Hueston, Cara, M (1) | O'Leary, Olivia, F (1)
| Cryan, John, F (1,2) | Nolan, Yvonne, M (1)
Adolescence is a critical period for postnatal brain maturation and thus susceptibility to
emotional and cognitive-related disorders. The nuclear receptor Nr2e1 (TLX) is a key regulator
of embryonic and adult hippocampal neurogenesis. Mice lacking TLX display deficits in adult
hippocampal neurogenesis as well as behavioural abnormalities. The ability of TLX to regulate
behaviour during adolescent development and whether there are sex-dependent effects
remains largely unexplored. The aim of this study was to determine the role of TLX in a series
of behavioural tasks in adolescent male and female mice with a spontaneous deletion of the
TLX gene (Nr2e1-/-). In order to capture potential deficits that may manifest during the
adolescent developmental period, behavioural testing commenced at postnatal day 28 and
continued until postnatal day 63. Results indicate that adolescent male and female Nr2e1-/mice were hyperactive in an open field (p<=0.0001) and that this effect persisted in adulthood
(p<=0.0001). Furthermore, male Nr2e1-/- mice exhibited a significant reduction in thigmotaxis
during adolescence (p<=0.0001) and adulthood (p<=0.0001). Impairments in motor performance
on the Rotarod developed in both male (p<=0.01) and female (p<=0.0001) Nr2e1-/- mice at the
onset of adulthood. Spontaneous alternation in the Y-maze, a hippocampal-dependant task was
impaired in male (p<=0.05) and female (p<=0.05) adolescent Nr2e1-/- mice but not in adulthood.
Hippocampal-dependent contextual fear conditioning was impaired in male adolescent Nr2e1/- mice only (p<=0.01) but this did not persist into adulthood. Nr2e1-/- mice also showed
impaired cued fear conditioning, a hippocampal-amygdala dependent cognitive process in both
male (p<=0.05) and female (p<=0.0001) Nr2e1-/- adolescent mice. These deficits persist in
adult male Nr2e1-/- mice (p<=0.0001). Together, these findings suggest TLX plays a key role in
cognitive and anxiety-like behaviour during adolescent development as well as in motor
performance which persists into adulthood.
This work was supported by Science Foundation Ireland (SFI/IA/1537).
(1) Department of Anatomy and Neuroscience University College Cork - Ireland | (2) Alimentary
Pharmabiotic Centre Biosciences Institute University College Cork - Ireland
O'Leary James D | [email protected]
A TIME AND A REGION-SPECIFIC ROLE OF ASTROCYTIC LACTATE IN THE
FORMATION AND MAINTENANCE OF POSITIVE AFFECTIVE MEMORIES
ASSOCIATED WITH COCAINE-ASSOCIATED CUES.
Benjamin, Boury-Jamot | Anthony Carrard | Jean Luc Martin | Olivier Halfon | Pierre J.
Magistretti | Benjamin Boutrel
Drug memories that associate contextual cues with the effects of drugs are known to shape
persistent drug seeking behaviors. Since the transfer of glycogen-derived lactate from
astrocytes to neurons is required for long-term memory (Suzuki et al., 2011), we recently
demonstrated that disrupting glycogenolysis in the basolateral amygdala (BLA) impaired the
acquisition and maintenance of positive affective memories associated with cocaine-associated
cues. Briefly, rats that received intra-BLA infusions of the inhibitor of glycogen phosphorylase,
1,4-dideoxy-1,4-imino-D-arabinitol (DAB 300 pmol/side) did not acquire a cocaine-induced
conditioned place preference (CPP). Most importantly, a double DAB infusion (15 minutes prior
and 5 hours after contextual re-exposure) in conditioned rats exhibiting a strong preference for
the cocaine compartment abolished the cocaine attractiveness for up to two weeks. Finally,
we demonstrated that drug memory was rescued by L-Lactate co-administration through a
mechanism requiring the synaptic plasticity related transcription factor Zif268, and
extracellular signal-regulated kinase (ERK) signalling pathway. We then tried to replicate our
observations by targeting the prefrontal cortex (PFC), but rats continued to exhibit a strong
preference for the cocaine compartment. However, recent evidence established that
consolidation of drug reward memories depended on successive phases (Gholizadeh et al, 2013),
with the BLA involved in the early phase and the PFC possibly involved in the late phase of
memory consolidation. To confirm this assumption in our model, rats were injected with DAB
(480 pmol) into the PFC fifteen minutes and twelve hours after the contextual re-exposure. In
contrast to rats injected with DAB 15 min/5h, those treated 15 min/12h exhibited a significantly
reduced exploration of the cocaine compartment. Taken together, these results highlight a
signaling role of astrocytic lactate in both acquisition and maintenance of cocaine-seeking
behavior following a BLA - PFC temporal pathway.
(1) Centre for Psychiatric Neuroscience - Department of Psychiatry - Lausanne University Hospital Lausanne Switzerland
Benjamin Boury-Jamot | [email protected]
INFLUENCE OF THE OVARIAN CYCLE AND ESTRADIOL ON BINGE EATING
EVOKED IN FEMALE RATS BY FOOD RESTRICTION FOLLOWED BY
FRUSTRATION STRESS
Micioni Di Bonaventura, Maria Vittoria (1) | Lutz, Thomas A (2) | Romano, Adele (3) |
D'Addario, Claudio (4) | Asarian, Lori (2) | Cifani, Carlo (1)
Eating disorders show marked gender differences (Klump et al 2008 Psych Med 38:1749-57) and
several epidemiologic studies suggest that binge eating episodes are more common in females
than in males. To further investigate the mechanisms underlying this sex difference, we used
an animal model first described by Cifani et al (2009 Psychopharm 204:113-125), in which bingeeating is evoked in female rats by 3 cycles of food restriction followed by frustration stress (15
min exposure to the sight of the palatable food). We aimed to determine whether binge eating
behavior (1) varies across the estrus cycle and (2) is influenced by estradiol (E2) in
ovariectomized (OVX) rats. Finally, using immunocytochemistry, we quantified the activation
of extracellular signal regulated kinase (ERK) signaling pathway in OVX rats treated with E2 or
oil, in basolateral (BLA) and the central (CeA) amygdala, paraventricular nucleus of
hypothalamus (PVN) and arcuate nucleus (ARC).
Restricted and stressed rats in estrus and OVX rats treated with E2 did not show binge eating
behavior in comparison to the control non-restricted and non-stressed rats. The lack of binge
eating behavior in estrous rats was accompanied by a significant decrease in ERK
phosphorylation in ARC, PVN and in the CeA, but not in BLA, in comparison to non-estrous rats
and to non-restricted and non-stressed animals.
Our findings show that binge eating does not occur during the estrous phase. Because this was
recapitulated in OVX rats treated with E2, they suggest that the inhibitory effect of E2 on eating
is partly responsible for the lack of bingeing. These results are consistent with reports in women
with bulimia nervosa (Edler et al 2007 Psych Med, 37:131-141) and extend our previous findings
and increase the validity of our model, that can be used in translational studies of the
mechanism of binge eating behavior.
(1) University of Camerino - Italy | (2) University of Zurich - Switzerland | (3) Sapienza University of
Rome - Italy | (4) University of Teramo - Italy
[email protected]
Micioni Di Bonaventura Maria Vittoria | [email protected]
EPIGENETIC REGULATION OF ADENOSINE A2A AND DOPAMINE D2
RECEPTOR GENE TRANSCRIPTION ON COMPULSIVE FOOD CONSUMPTION
Micioni Di Bonaventura, Maria Vittoria (1) | Pucci, Mariangela (2) | Giusepponi, Maria Elena
(1) | Lambertucci, Catia (1) | Volpini, Rosaria (1) | Maccarrone, Mauro (3) | D'Addario,
Claudio (2) | Cifani, Carlo (1)
Satisfactory treatments for eating disorders, such as binge eating disorder and bulimia nervosa,
are not available at present. Using a well-characterized animal model of binge eating, we
investigated the epigenetic regulation of the adenosine A2A Receptor (A2AAR) and dopamine D2
(D2R) gene.
The animal model included four groups (rats fed normally, and then stressed or not, rats
exposed to cycles of restriction/refeeding, and then stressed or not).
Gene expression analysis carried out on the amygdala complex of restricted and stressed rats
revealed a significant increase of A2AAR and D2R mRNA when compared to non-stressed and
non-restricted rats. Administration of the A2AAR agonist (VT 7) induced in restricted and stressed
rats a significant increase of A2AAR and D2R mRNA levels when compared to vehicle group,
whereas a significant decrease in rats pre-treated with the A2AAR antagonist (ANR 94) was
observed.
Pyrosequencing analysis revealed a significant reduction of the % of DNA methylation at A2AAR
promoter region in restricted and stressed compared to the non-stressed and non-restricted
animals. We did not find any difference in D2R DNA methylation among different groups.
Significant changes in the DNA methylation status of A2AAR promoter were found in restricted
and stressed rats after administration of VT 7 or ANR 94. We observed a decrease of DNA
methylation in VT 7 treated rats and a hypermethylation in ANR 94 rats with respect to the
vehicle group.
The increase in A2AAR mRNA observed in restricted and stressed rats could be due to a
compensatory mechanism to counteract the effect of binge eating, suggesting that the A2AAR
activation, inducing receptor gene up-regulation, could be relevant to reduce food consumption.
We here demonstrated for the first time the epigenetic regulation of A2AAR in an animal model
of binge eating.
(1) University of Camerino - Italy | (2) University of Teramo - Italy | (3) Campus Bio Medico - Italy |
University of Teramo - Teramo
[email protected]
Micioni Di Bonaventura Maria Vittoria | [email protected]
INTERACTIONS OF OXYCODONE AND HIV-1 TAT EXPRESSION ON STARTLE,
SENSORIMOTOR GATING, LOCOMOTOR ACTIVITY AND ORAL OXYCODONE
SELF-ADMINISTRATION IN MICE
Enga, Rachel M. (1) | Knapp, Pamela E. (1) | Hauser, Kurt F. (1) | Beardsley, Patrick M. (1)
Abuse of prescription opioids, such as oxycodone (OXY), has increased in recent years. In HIVinfected individuals there is evidence of increased risks of developing opiate dependency,
worsened cellular damage, and behavioral deficits symptomatic of HIV-associated
neurocognitive disorders (HAND), in part, likely attributable to the interaction of opiates with
the neurotoxic HIV-1 Tat protein. Previously, in agreement with clinical evidence of HANDrelated sensorimotor gating deficits, we found significant deficits in prepulse inhibition of the
startle reflex (PPI), an operational measure of sensorimotor gating, in transgenic mice that
centrally expressed the HIV-1 Tat protein upon administration of a doxycycline (DOX)containing diet. We subsequently hypothesized that chronic exposure to OXY sufficient to
induce physical dependence would engender greater PPI deficits in Tat-expressing vs Tat-null
mice. After a 2-week DOX diet, a 10-day escalating OXY dosage regimen (9-33 mg/kg, s.c.) was
used to induce physical dependence in DOX-fed Tat(+), Tat(-), and C57BL/6J (i.e., B6) mice.
Chronic OXY significantly (p<=0.05) increased locomotor activity, but did not affect startle nor
PPI significantly in any group. Precipitating withdrawal with naloxone (1 mg/kg, s.c.) also did
not affect PPI in any group. However, precipitated withdrawal did significantly reduce
bodyweight and the startle reflex in B6 and Tat(-) mice compared to vehicle challenge that was
not observed in Tat(+) mice. These results suggest that Tat-expressing mice may actually be
more resistant to opiate dependency effects. In other studies that employed a novel oral
operant self-administration procedure, results with B6 mice demonstrated intoxicating (e.g.,
Straub tail, hyperlocomotion) levels of volitional OXY intake (1 mg/mL) under fixed-ratio 4 (FR
4) maintenance conditions, and progressive ratio break points exceeding FR 128, during 3-h
experimental sessions. Ongoing studies will examine oral oxycodone self-administration in HIV1 Tat-expressing mice to compare to performances of the B6 mice.
(1) Virginia Commonwealth University - USA
Enga Rachel M. | [email protected]
NEUROTENSIN RECEPTOR AGONISTS MEDIATE FEAR-INDUCED
ULTRASONIC VOCALIZATIONS IN MALE WISTAR RATS
Steele, Floyd, F (1) | Whitehouse, Shannon, C (1) | Ritchie, Taylor, A (1) | Aday, Jake, S (1)
| Prus, Adam, J (1)
Neurotensin (NT) is a peptide neurotransmitter that interacts with brain monoamine
neurotransmitter systems. It has been demonstrated that neurotensin type 1 and type 2
receptor agonists influence animal models of psychological disorders and pain regulation,
respectively (Binder et al., 2001; Boules et al., 2013). Our lab has already shown that the
systemic administration of the selective neurotensin type 1 receptor agonist PD149163 can
attenuate the number of fear-induced 22-kHz ultrasonic vocalizations (USVs) produced by male
Wistar rats (Prus et al., 2014). A reduction in the number of 22-kHz USV calls is indicative of an
anxiolytic effect (Brudzynski, 2009). The current study uses the USV model to evaluate the
effects of PD149163 and endogenous NT when administered into the lateral ventricle of male
Wistar rats. Both PD149163 and NT were shown to attenuate USV calls when administered into
the lateral ventricle. PD149163 was found to have a higher potency than NT in the USV model.
In addition, while 100ng of PD149163 significantly reduced USV calls, it did not reduce
locomotion on an open field that was surrounded by bright lighting. These data suggest
neurotensin receptor activation is a putative mechanism for novel pharmacological treatments
of anxiety disorders.
(1) Northern Michigan University United States
Email: [email protected] | [email protected] | [email protected] | [email protected] | [email protected]
Prus Adam J | [email protected]
OPTOGENETIC STIMULATION OF THE SUBTHALAMIC NUCLEUS IMPAIRS
THE MOTIVATION FOR FOOD IN RATS
Tiran-Cappello, Alix (1) | Pelloux, Yann (1) | Montanari, Christian (1) | Baunez, Christelle (1)
Among the basal ganglia, the subthalamic nucleus (STN) is a well-known structure in the
treatment of Parkinson's disease as it represents the major target for application of deep brain
stimulation (DBS). Over the past few years, the increasing evidence that STN is critical for
limbic and associative processes, lead to investigate its relevance as a potential target for the
treatment of addiction and compulsive disorders. It has been established that the inactivation
of the STN by various methods (lesion and high-frequency DBS) enhances the motivation for
food and reduces the motivation for cocaine (for review Pelloux and Baunez, 2013). These
opposite properties regarding natural reward and drugs of abuse appear to be a unique feature
of the STN. In order to further characterise its role in the modulation of reward and motivation,
we used optogenetic tools to modulate the activity of the rat STN. We injected a fast kinetic
channelrhodopsin (ChetaTC) in the STN and tested whether high-frequency stimulation (130Hz)
could enhance food motivation in a similar manner to what was observed with DBS. For this
purpose, we subjected the rats to FR5 and PR schedules, using sweet food pellets as reinforcer,
to monitor their willingness to work despite a low or increasing amount of effort, respectively.
The preliminary results suggest that optogenetic stimulation, from 20 to 130Hz, reduces the
motivation for food, in line with what could be expected from a stimulation (i.e. opposite
effects to that of STN lesion). Interestingly, optogenetic and electrical stimulation at 130Hz
induce opposite behavioural responses, suggesting optogenetic stimulation enhances neuronal
activity within the STN in contrast to electrical DBS. These results should provide further
understanding of the physiology that underlies DBS and the contribution of STN in motivational
processes.
(1) Institut de neurosciences de la Timone - France
Tiran-Cappello Alix | [email protected]
BUSPIRONE MAINTENANCE REDUCES SEXUAL RISK-TAKING BUT DOES NOT
ALTER THE ABUSE-RELATED EFFECTS OF COCAINE IN COCAINE USERS
Bolin, Levi, B (1) | Lile, Joshua, A (1) | Marks, Katherine, R (1) | Rush, Craig, R (1) | Stoops,
William, W (1)
Aim: The anxiolytic drug buspirone reduces delay discounting in rats and blunts the reinforcing
effects of cocaine in some preclinical studies suggesting that it may have utility in the
treatment of cocaine-use disorders. This study determined whether buspirone might mitigate
impulsive, risky sexual decision-making in cocaine users on a sexual delay-discounting
procedure. The effects of buspirone maintenance on the abuse-related and physiological
effects of cocaine were also tested.
Methods: Nine current cocaine users (N = 9) completed a repeated-measures, inpatient protocol
in which sexual delay discounting was assessed following three days of maintenance on placebo
and buspirone (30 mg/day) in counterbalanced order. The reinforcing, subject-rated, and
physiological effects of placebo and intranasal cocaine (15 and 45 mg) were also assessed during
buspirone and placebo maintenance.
Results: Buspirone reduced discounting of delayed condom use for hypothetical sexual partners
that were categorized as most likely to have a sexually transmitted infection and least sexually
desirable. Cocaine functioned as a reinforcer and increased ratings of positive subjective
effects. Buspirone maintenance generally did not impact the abuse-related behavioral effects
of cocaine, but it blunted cocaine-induced increases on cardiovascular measures.
Conclusion: These preliminary findings suggest that buspirone may be useful for managing
impulsive, HIV-risk behavior associated with cocaine use.
Supported by NIDA Grants: R21 DA034095, T32 DA035200, TL1 TR000115, and K02 DA031766.
Main Theme: C.17.x. Addiction: Behavioral pharmacology.
(1) University of Kentucky USA
[email protected]
Bolin B. Levi | [email protected]
FROM ANIMAL MODELS TOWARDS SCHIZOPHRENIA: SPATIAL NAVIGATION
IN VIRTUAL REALITY
Fajnerova, Iveta | Rodriguez Mabel | Levcik David | Brom Cyril | Horacek Jiri | Spaniel Filip
| Stuchlik Ales | Vlcek Kamil
Cognitive deficit is considered one of the core symptoms of schizophrenia and related psychotic
disorders that affects several cognitive domains. Cognitive deficit offers very useful
methodological approach for comparative studies. Deficit in visuo-spatial abilities has been
demonstrated in schizophrenia patients and similar behavioral changes were observed in animal
models of schizophrenia. In order to assess complex spatial abilities in schizophrenia and
compare their results with data obtained in previous animal studies, we designed two virtual
reality tasks adopted from the animal research.
We recruited a study group (SZ) of first-episode schizophrenia patients and a control group of
healthy volunteers (HC) matched for age, sex, education and gaming experience. At baseline
day all participants completed a neuropsychological assessment and SZ symptoms were
evaluated by PANSS and GAF scales. The second day all participants underwent a short pretraining followed by two virtual tasks: 1. Stable arena - inspired by the Morris water maze
hidden goal paradigm. 2. Rotating arena - inspired by the Carousel maze modified from
avoidance to a preference task.
Results of both virtual tests showed significant decline in spatial abilities in SZ compared to HC
in all test phases. According to the PCA analysis, data obtained in the stable arena form a
cluster together with learning and memory tests, while the rotating arena seems to be more
related to performance tests dependent on flexibility, timing and psychomotor speed.
Visuospatial deficit observed in SZ patients correlates with the results of standard
neuropsychological assessment, and with the findings of other spatial studies in schizophrenia
patients and animal models.
The study was supported mainly by IGA MZCR grant NT13386, by the project "National Institute
of Mental Health (NIMH-CZ)" - grant number ED2.1.00/03.0078 of the ERDF, and by the
institutional support from the Czech Academy of Sciences (RVO: 67985823).
National Institute of Mental Health and Third Faculty of Medicine - Charles University in Prague Czech Republic - National Institute of Mental Health Czech Republic - Institute of Physiology - CAS Czech Republic
[email protected] | [email protected] | [email protected] | [email protected] |
[email protected]
Fajnerova Iveta | [email protected]
COMPARISON OF ANTERIOR THALAMIC NUCLEI AND MAMMILLOTHALAMIC
TRACT LESIONS
Perry, Brook, A L (1) | Mercer, Stephanie, A (1) | Barnett, Sophie, C (1) | DalrympleAlford,
John, C (1)
The anterior thalamic nuclei (ATN), and the mammillothalamic tract (MTT) projection to the
ATN from the mammillary bodies (MB), are key parts of the extended hippocampal system. The
MTT are typically associated with diencephalic amnesia after stroke, whereas a combination of
ATN degeneration and MB injury is associated with the amnesic Korsakoff’s syndrome. Separate
rat studies suggest that ATN lesions may produce more severe memory deficits than MTT lesions.
Here, both radiofrequency MTT (n=9) and neurotoxic ATN (n=8) lesions produced deficits in the
working memory versions of the water maze and RAM, but the RAM deficit was more pronounced
in the ATN group. Only ATN lesions, however, impaired reference memory in the water maze.
Using a modified RAM task that is sensitive to retrosplenial cortex lesions, we found that both
ATN and MTT lesions markedly reduced IEG expression across the retrosplenial cortex, there
was a graded effect ATN <= MTT <= Control in hippocampal CA1, and only ATN lesions reduced
zif268 in the anterior cingulate cortex. ATN, and especially MTT lesions, reduced NeuN counts
in the MB. This first comparison of ATN and MTT lesions confirms that ATN lesion effects are
generally more severe, whereas relatively minor differences in IEG hypoexpression resulted
from these lesions. Hence the severe amnesia associated with MTT lesions in humans may
depend on the extent of additional direct injury to the ATN and/or other adjacent nuclei.
Diaschisis in the retrosplenial cortex may influence only a subset of memory tasks.
(1) Psychology Department - University of Canterbury, Christchurch - New Zealand
[email protected]
Perry Brook A L | [email protected]
THE EFFECTS OF CHOLINERGIC LESIONS OF THE HIPPOCAMPUS ON
EPISODIC-LIKE AND CONTEXT-PLACE MEMORY IN A NEW BEHAVIOURAL
APPARATUS
Seel, Sabrina, V (1) | Eacott, Madeline, J (1) | Easton, Alexander (1)
Animals’ memory can be assessed through their spontaneous exploration of novel configurations
of an environment. These types of tasks are used in memory research to develop therapies for
memory loss in neurodegenerative diseases. The problem with these tasks is that exploration
can be driven by other factors such as the stress that is induced by the amount of handling. In
a typical memory task animals only do one trial per day, which means that many animals are
required to maintain statistical power and accumulation of data is slow.
This study sought to determine how effectively episodic memory can be tested in a multiple
trial apparatus in intact and lesion animals. Previous studies have shown that tasks of episodiclike (what-where-which) memory are impaired by lesions of the fornix (Eacott & Norman, 2004)
and the hippocampus (Langston & Wood, 2010). However, rats with lesions of the cholinergic
projections to the hippocampus perform well on the episodic-like task. Nonetheless they are
impaired in a task that involves memory for the conjunction of context and place (where-which)
(Easton et al., 2011). Therefore, acetylcholine may only be necessary in some hippocampaldependent processes.
Here we replicate this earlier finding in an apparatus where multiple trials are run in a single
session, meaning a significant (approx. 50%) reduction in animal numbers. The findings
demonstrate the reliability of the dissociation within the hippocampus based on cholinergic
function within the hippocampus, and verifies the new apparatus as assessing episodic-like
memory in the same manner as earlier studies, improving the reliability of the task and having
a significant 3Rs benefit.
(1) Durham University - UK
Seel Sabrina V. | [email protected]
EFFECTS OF XANTHOTOXIN ON MEMORY PRECESSES AND OXYDATIVE
STRESS
Budzyńska, Barbara | Boguszewska-Czubara Anna | Kruk-Słomka, Marta | Skalicka-Woźniak,
Krystyna | Wydrzyńska-Kuźma Małgorzata | Biała, Grażyna
Xanthotoxin (8-methoxypsoralen, 8-MOP), is a furanocoumarin found in many medicinal plants
and is used in the treatment of psoriasis, vitiligo, and cutaneous T-cell lymphoma. This drug
also possesses slight antioxidative activity as evidenced from in vitro studies. Literature data
have demonstrated that xanthotoxin possess inhibitory activities on monoaminooxydase (MAO),
butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). BuChE and AChE degrade
acetylcholine which prevents the formation of senile plaques in Alzheimer's disease.
The aim of the present study was to examine the effects of an acute administration of
xanthotoxin on memory processes as well as on memory impairment induced by injection of
scopolamine in the passive avoidance (PA) paradigm in male Swiss mice. We also assessed the
relation of this drug in the level of oxidative stress in brain. Xanthotoxin was purified by highperformance counter-current chromatography from methanol extract of fruits of Angelica
officinalis. We revealed that acute injections of xanthotoxin at the dose 2.5 mg/kg, i.p.,
improved processes of memory acquisition, whereas the doses of 2.5 and 5 mg/kg improved
processes of memory consolidation in the PA task. Moreover, xanthotoxin administered acutely
at the dose of 2.5 mg/kg prior to the injection of scopolamine (1 mg/kg) improved memory
acquisition and consolidation impaired by scopolamine. Oxidative stress was assessed by
determination of antioxidant enzymes (glutathione peroxidases (GPx), superoxide dismutase
(SOD) activities as well as of malondialdehyde (MDA) concentration in the whole brain. The
results of our research suggest xanthotoxin to be an interesting therapeutical option in disorders
with memory deficits.
This study was supported by grant no 2014/13/B/NZ4/01249 from the National Science Centre,
Poland.
Department of Pharmacology and Pharmacodynamics - Medical University of Lublin - Poland |
Department of Medical Chemistry - Medical University of Lublin - Poland
Budzynska Barbara | [email protected]
LONG LASTING EFFECTS OF SUBCHRONIC ADMINISTRATION OF
MEPHEDRONE WITH MDMA IN MICE
Biala, Grazyna (1) | Kruk-Slomka, Marta (1) | Michalak, Agnieszka (1) | Budzynska, Barbara
(1)
Mephedrone (4-methylmethcathinone) is a widely abused novel psychoactive drug,
semisynthetic derivative of cathinone, whereas 3,4-methylenedioxymethamphetamine (MDMA;
ecstasy) is an amphetamine derivative drug with entactogenic, empathogenic and
hallucinogenic properties, commonly consumed at rave parties in a polydrug abuse pattern.
Moreover, these drugs show close structural and mechanistic convergence which can contribute
even to life-threatening interactions. However, there is no research focused on evaluating long
lasting effects of co-administration of both drugs.
The aim of the present study was to examine the long lasting effects of chronic administration
of mephedrone co-injected with a single dose of MDMA on depressive-like behaviors in the
forced swim test (FST), memory consolidation in the passive avoidance (PA) paradigm and
anxiety-like behaviors in the elevated plus maze (EPM) test in mice. At first, we showed that
subchronic (7 days) administration of mephedrone (5 mg/kg) with MDMA (1 mg/kg, day 7th)
impaired consolidation of memory and learning processes in the PA task observed on the 7th
day after last drugs injections. In the second series of our experiment, long lasting anxiety-like
behaviors were observed in mice injected subchronically with mephedrone (0.5 mg/kg)
together with a single injection of MDMA (0.5 mg/kg) in the EPM test. Furthermore, co-injection
of mephedrone (2.5 mg/kg, days 1-7) with MDMA (2.5 mg/kg, day 7th) exerted an antidepressive
effect on the last day of administration, whereas on the 14th day after drugs cessation we
observed increase in immobility time in the FST. In conclusion, we may suggest that
subchronically administered mephedrone combined with a single injection of MDMA exert long
lasting effect on neurotransmission in the central nervous system, however, future biochemical
studies are required to explore this hypothesis.
This study was supported by grant no 2013/11/B/NZ7/04837 from the National Science Centre,
Poland and by the statutory activity of the Medical University of Lublin, Poland.
(1) Medical University of Lublin - Chair and Department of Pharmacology and Pharmacodynamics Poland
[email protected]
Biala Grazyna | [email protected]
GHRELIN AND OREXIN SYSTEMS PARTICIPATION IN FEAR AND ANXIETY
BEHAVIOR - MONITORING OF AVERSIVE ULTRASONIC VOCALIZATION IN
RATS
Havlickova, Tereza (1) | Jerabek, Pavel (1) | Krsiak, Miloslav (1) | Sustkova, Magdalena (1)
Aims: Orexigenic peptides ghrelin and orexin exhibit central neurobiological effects which are
involved in food intake, reward, learning and mood. Both peptides elicit mostly pro-anxiety
effects. Thus we wanted to test the potential anxiolytic-like effects of the ghrelin receptor
antagonist (JMW1959) and orexin receptor antagonist (SB334867) which has yet to be done and
for the first time use the aversive ultrasonic vocalization (AUV) in rats for testing these peptides
mechanisms participation.
Methods: The automatic chamber ANL-937-1 Ultrasonic Vocalization Detector (Med Associates
Inc.) was used with bat detector set to 22 kHz (corresponding to rat's aversive ultrasonic
communication). One day before the experiment the aversive behavior was established (i.e.
rats were individually exposed in the chamber for 7min to 6 electro-shocks). The aversion was
fixed on the next day (1 shock during 1min exposure), and thereafter antagonists JMW2959 (0.6,
6; 12 mg/kg) and SB334867 (1; 10; 20 mg/kg) or ghrelin (30; 300 μg/kg) or saline were i.p.
applied. Thirty minutes later the rat´s AUV was measured again in the chamber for 10min (no
electro-shocks). The anxiolytic-like effects were considered compared to the control/saline
rats (6 - 10 rats in the groups).
Results: The ghrelin antagonist significantly decreased AUV in doses 6 mg/kg (decrease of
74.2%) and 12 mg/kg (decrease of 62.8%) versus control. The observed SB33487-induced
anxiolytic-like and ghrelin-induced anxiety-like effects were not significant.
Conclusion: We have found that ghrelin antagonist significantly decreased the rat´s AUV, which
supports the idea, that ghrelin antagonism might be used for prevention of distress and anxietyinduced overeating and drug consumption.
Acknowledgements: This study was supported by PRVOUK34, 260168/SVV/2015, GAUK 54313.
(1) Department of Pharmacology - Third Faculty of Medicine - Charles University in Prague - Czech
Republic
[email protected]
Havlickova Tereza | [email protected]
PREVENTION AND REVERSAL OF ESCALATED COCAINE SELFADMINISTRATION BY CRF R1 ANTAGONIST IN SOCIALLY DEFEATED MICE
Han, Xiao (1) | DeBold , Joseph (1) | Miczek, Klaus (1)
Social defeat stress can result in escalated cocaine self-administration in rodents and also
induces long-term adaptations in the mesolimbic dopamine system. Corticotrophin releasing
factor (CRF) has been shown to be closely associated with stress-induced escalation of drug use.
CRF receptor 1 (CRF R1) antagonists can block intermittent social defeat stress-induced cocaine
“binge” in rats. However, the role of CRF R1 during different phases of stress-induced cocaine
self-administration still remains to be defined. The current study examines the effects of CRF
R1 antagonist on escalated intravenous cocaine self-administration as a result of exposure to
social defeat stress in mice. (1) CRF R1 antagonism (CP 376,395, 15mg/kg) given 30 min prior
to each social defeat episode prevented stress-induced cocaine self-administration in mice. (2)
Administration of CP 376,395 (5 mg/kg and 15 mg/kg) 10 days after the last episode of social
stress and dose dependently reversed the escalation of cocaine intake. (3) To further explore
the role of CRF R1 in specific brain sites, CP 376,395 (0.5 μg/ 0.2 μl and 1 μg/ 0.2 μl) was
delivered directly into the ventral tegmental area (VTA) 10 min before cocaine selfadministration session 10 days after the last stress. Intra-VTA antagonism of CRF R1 was
sufficient to reverse social defeat stress-induced escalated cocaine self-administration during
the expression phase. These findings suggest that CRF R1 exerts multiple roles during initial
reaction to social stress and in long-term neuroadaptations that are relevant to escalated
cocaine self-administration, providing a potential target for therapeutic inventions for stressinduced drug use disorders.
Acknowledgement:
This research is supported by NIDA grant # DA 03174, PI. Klaus A. Miczek. The authors declare
no conflict of interest.
(1) Tufts University - USA
Han Xiao | [email protected]
A CONTINUAL TRIAL APPARATUS TO REDUCE THE NUMBER OF MICE USED
IN RECOGNITION MEMORY TASKS
Chan, Michele, SY (1) | Eacott, Madeline, J (1) | Sanderson, David (1) | Sun, Mu (2) | Easton,
Alexander (1)
Spontaneous object recognition task and its variants are widely used to investigate different
aspects of memory in Alzheimer’s disease and other neurodegenerative conditions. Capitalising
on an animals’ natural preference towards novelty, successful recognition is demonstrated
when an animal preferentially explores the novel over the familiar object. Previous studies
(Ameen-Ali et al., 2012) in rats have adapted the standard procedures to produce the continual
trials apparatus. By running multiple trials within a testing session, Ameen-Ali et al.,
successfully reduced the variance normally associated with performing one trial a day. Stress
induced variance was also reduced in the continual trials apparatus because animals were only
handled at the start and end of the session. This refinement produced more reliable data and
reduced the number of animal required in these tasks by nearly 50%.
To maximise the potential of the continual trials apparatus, especially in research of
neurodegenerative diseases, we have adapted the apparatus to test mice. Similar to AmeenAli’s et al. study, our findings have shown that with the apparatus, equivalent statistical
significance could be achieved with smaller numbers of mice. This is true in animals at different
ages, including older (10 month) animals where behaviour in spontaneous tasks can be difficult
to assess. We have also validated the apparatus using a mouse model of Alzheimer’s disease
(TASTPM mice). In contrast to some previous reports in the literature, these animals were able
to perform the spontaneous object recognition and object location tasks at 7 and 10 months of
age, suggesting that the increased reliability of performance on these tasks can help clarify
discrepancies in the literature.
This study, therefore, demonstrates how a simple procedural change can refine a behavioural
task leading to reduction in animal numbers. In addition the improved reliability provides
clearer understanding of the neural basis of recognition memory.
(1) Durham University | (2) GlaxoSmithKline
Chan Michele SY | [email protected]
IMPAIRED PSYCHOMOTOR AND COGNITIVE FUNCTIONS IN ADULT RATS
TREATED WITH ESCALATING LOW THC DOSES DURING ADOLESCENCE
Poulia, Nafsika (1) | Delis, Foteini (1) | Pitsikas, Nikolaos (2) | Antoniou, Katerina (1)
Exposure to cannabis during the adolescent developmental window has been associated with
psychiatric disorders later in adulthood (Rubino et al., 2012, J.
Psychopharm. 1:177-88). The majority of the side effects associated with cannabis abuse may
be ascribed to its main psychoactive component, delta-9-tetrahydrocannabinol (THC).
Experimental studies have shown that THC during development induces long-term behavioral
impairments and neurobiological alterations in adulthood. In this study we evaluated the
behavioral effects of low THC doses administered during adolescence, in adult rats. Additionally,
we aim to associate these behavioral effects with specific neurobiological indices. THC
treatment began on PND 35 and lasted until PND 45. Male rats received escalating low doses of
THC twice a day (0.3 mg/kg PND 35-37; 1 mg/kg PND 38-41; 3 mg/kg PND 42-45) or vehicle. On
PND 75, a subset of rats was exposed to a battery of behavioral tests including open field
paradigms and object location task (Galanopoulos et al., 2014, Pharm. Biochem. Behav. 124:5866), while specific rat brain regions were isolated from another subset of rats for
neurobiological measures.
THC-treated rats displayed increased reactivity to a novel environment, compared with the
control group, in adulthood. In particular, in these rats enhanced horizontal and vertical
activity was observed while center time was also increased. Both THC and vehicle-treated rats
were able to habituate to the novel environment, but it took longer for the THC group to reach
the habituation plateau. In the novel location task, THC-treated rats had lower preference for
a known object located in a novel position over a familiar position, compared with vehicle. Our
results have shown that exposure to THC at escalating low doses during adolescence induces
psychomotor stimulation and impairments in emotionality and cognitive function in adulthood.
These behavioral findings will be associated with specific neurobiological indices.
(1) Department of Pharmacology - Faculty of Medicine - Univ. of Ioannina - Greece | (2) Univ of
Thessaly - Greece
Poulia Nafsika | [email protected]
BEHAVIORAL EFFECTS OF THE REFRIGERANT VAPOR 1,1,1,2TETRAFLUROETHANE (R134A) IN MICE
Shelton, Keith, L (1) | Tracy, Matthew, E (1) | Richardson, Kellianne, J (1)
Inhalants are a large class of volatile and gaseous compounds defined only by their route of
abuse. Inhalant abuse can cause severe, long-term neurological consequences including
memory deficits, neuropathies and diffuse white matter loss. Despite the magnitude of the
problem, virtually nothing is known about the behavioral effects of many frequently abused
inhalant chemicals at those concentrations which are subject to abuse. The refrigerant 1,1,1,tetrafluroethane (R134a), has widespread use in automobile, home and commercial
refrigeration systems. Although banned in new automobile air conditioning systems in 2013 by
the European Commission due to it’s potency as a greenhouse gas, it is still utilized in new
vehicles produced in most of the world and will consequently remain available for decades.
Intentional inhalational abuse of R134a vapor from air conditioner recharging kits or more
commonly from “computer keyboard duster” canisters produces intoxication but also poses a
significant risk of death. However, there is little objective scientific data on the intoxicating
effects of R134a exposure. The present study examined the effect of exposure to up to 30%
R134a mixed with supplemental oxygen on both food-reinforced operant behavior as well as
locomotor activity in C57BL/6J mice. Pre-exposure to 20 min of R134a vapor produced a
concentration-dependent depression of operant responding with lever-pressing entirely
suppressed by 20% R134a. In an open field locomotor activity assay, inhalation of R134a
produced changes in locomotor activity within 4 min of initiation of exposure. Concentrations
of 10-20% R134a initially increased and then subsequently decreased locomotor activity,
whereas 30% R134a produced only locomotor suppression. Concentrations of both 20% and 30%
R134a also produced an anxiolytic-like increase in time spent in the center zone of the open
field. These data suggest that R134a inhalation has CNS depressant-like behavioral effects
similar to those produced by benzodiazepines and other abused inhalant vapors.
(1) Virginia Commonwealth University - Richmond Virginia - USA
Shelton Keith L | [email protected]
ROLE OF BRAIN DERIVED NEUROTROPHIC FACTOR IN FOOD REWARDED
BEHAVIOUR, IMPLICATIONS FOR THE STUDY OF OBESITY
Olarte-Sánchez, Cristian, M (1) | Valencia-Torres, Lourdes (1) | Heisler, Lora, K (1)
Accumulating evidence support the idea that obesity is influenced by very complex behaviours
which are controlled by the interaction of both the homeostatic and reward-related processes.
Homeostatic mechanisms converge within the hypothalamus and hindbrain and within these
brain regions, the levels of Brain-derived neurotrophic factor (BDNF) and its receptor
Tropomyosin receptor kinase B (TrkB) are influenced by energy status. The mesolimbic
dopamine system, which is related with the regulation of both motivated and reward seeking
behaviour, is also correlated with the consumption and motivation for drugs and palatable food
intake. BDNF and TrkB are expressed in this reward system and it has been shown to influence
both drug addiction (Graham et al., 2007) and high palatable food intake. For instance selective
depletion of BDNF in the Ventral tegmental area (VTA) produced hyperphagia and increased
body weight when animals were fed with high palatable food (Cordeiras and Rios 2011).
Furthermore BDNF over-expression in the VTA reduced sucrose intake that was interpreted as
a reduction of anhedonia (Taliaz et al., 2013).
Here we specifically removed BDNF in the VTA using BDNF-flx mice infused with adenoassociated viral (AAV) vectors encoding for Cre recombinase or a mCherry fluorescent protein
using stereotaxic surgery. A month later animals were evaluated on performance on the
progressive-ratio (PR) schedule in which the response requirement increases progressively for
successive reinforcers. The number of responses in this schedule is correlated with the
individual’s motivation. We found that the VTA BDNF deleted group gave more responses in
order to obtain palatable food compared with controls. These findings provide further support
that BDNF is related not only with the regulation of homeostatic but also hedonic feeding.
(1) University of Aberdeen UK
Olarte-Sanchez Cristian M | [email protected]
EFFECTS OF THE NOVEL DEHYDROEPIANDROSTERONE (DHEA) ANALOGUE
BNN27 ON DIFFERENT MEMORY COMPONENTS AND ON SCOPOLAMINEINDUCED AMNESIA IN A RECOGNITION MEMORY TASK IN RATS
Pitsikas, Nikolaos | Gravanis, Achilleas
BACKGROUND & OBJECTIVES: Consistent experimental evidence suggests the involvement of
neurosteroid dehydroepiandrosterone (DHEA) in cognition. BNN27 is a novel DHEA analogue,
which devoid of steroidogenic activity and its neurotrophic effect has been observed. Its role,
however, in learning and memory has not yet established. Thus, the present study was designed
to investigate the effects of BNN27 (1, 3 and 10 mg/kg) on rats’ recognition memory.
METHODS: For this purpose, the novel object recognition task (NORT) was used.
RESULTS: Intraperitoneal (i.p.) administration of BNN27 (3 and10 mg/kg) antagonized delaydependent deficits in the NORT in the normal rat, suggesting that this DHEA analogue affected
acquisition, storage and retrieval of information. In addition, BNN27 (3 and 10 mg/kg, i.p.)
counteracted the scopolamine [0.2 mg/kg, subcutaneously (s.c.)]-induced performance deficits
in this recognition memory paradigm.
CONCLUSIONS: The present results indicate that BNN27 may modulates different aspects of
recognition memory and suggest that its interaction with the cholinergic system is relevant to
cognition.
Department of Pharmacology - School of Medicine , University of Crete - Greece
Pitsikas Nikolaos | [email protected]
THE ASSOCIATION BETWEEN PARTICIPANT RECRUITMENT VARIABLES AND
INVITATION TO PARTICIPATE IN SUBSTANCE ABUSE RESEARCH: A
RETROSPECTIVE ANALYSIS
Alcorn III, Joseph, L (1) | Lile, Joshua, A (1) | Stoops, William, W (1) | Rush, Craig, R (1)
Very little work has systematically examined how screening and recruitment methods
contribute to successful identification of participants for in-person screening and subsequent
admission into research protocols. In order to most effectively identify individuals to participate
in human behavioral pharmacology research, we evaluated current screening and recruitment
methods.
This retrospective analysis explored the relationship between variables collected during
confidential phone interviews and subsequent invitations to complete in-person screening for
human behavioral pharmacological research. Independent variables included age, cocaine use,
gender and referral method. We predicted that males, as compared to females, would
represent a larger percentage of callers, especially for those reporting cocaine use. We also
predicted that referral via friend or family member would be associated with higher likelihood
of subsequent in-person screening.
We sampled 1035 individuals from the community within the past calendar year. Age did not
impact invitation to screening. Males represented a larger percentage of individuals invited to
screen (20.7% of total). Males were also more likely to report past month and year cocaine use
(27.5% and 31.9% of total, respectively). Prior participation was the recruitment method that
most likely resulted in invitation to subsequent screening (9% of total screens), but when past
participants were removed from the dataset, referral by friend/family member was most likely
to result in invitation for subsequent screening. These results reveal that men are more likely
to be invited to screen for our research protocols than women and that prior participation
increases the likelihood of invitation to further screening for other research. Future recruitment
efforts should be targeted to increase the proportion of females invited for in-person screening,
as well as increase the identification of new participants via friend/family referral.
Supported by NIDA Grants R01 DA025591 R01DA025032, R01DA032254, R01DA033394,
R21DA035481, R01DA036827, T32 DA035200 (CRR) R21DA034095, R21DA035376, R01DA036553
(WWS), and R01DA033364 (JAL).
Alcorn III Joseph L. | [email protected]
A GATING ROLE OF MEDIODORSAL THALAMUS FOR RIPPLE-ASSOCIATED
HIPPOCAMPAL-CORTICAL INFORMATION TRANSFER
Yang, Mingyu (1) | Logothetis, Nikos, K (1) (2) | Eschenko, Oxana (1)
Hippocampal sharp wave-ripple complexes (SPW-Rs) have been postulated to be involved in
hippocampal-cortical information transfer underlying declarative memory consolidation. Our
recent neural event-triggered fMRI study showed that occurrence of SPW-Rs was associated
with activity suppression in a number of subcortical regions, including thalamus. Description of
such specific activation/deactivation pattern of the whole-brain activity associated with SPWRs extended the predominant view on the SPW-Rs as indicators of hippocampal-cortical
functional connectivity, and SPW-R has been suggested to indicate a global network state
supporting declarative memory. The midline thalamic nuclei have been implicated to play a
role for learning and memory. However, it remains unexplored how thalamic neural activity
contributes to hippocampal-cortical dialogue. The medial dorsal nucleus of thalamus (MD)
receives input from the entorhinal cortex and is reciprocally connected with the prefrontal
cortex (PFC). The MD anatomical connectivity combined with the results of MD lesion studies
suggested a critical role of MD for associative and mnemonic functions. In the present study,
we characterized MD neural activity associated with hippocampal SPW-Rs. We performed
simultaneous extracellular electrophysiological recordings in MD and hippocampus in urethaneanesthetized and behaving rats. We then examined the firing rate modulation of the MD single
units (n = 151) around SPW-Rs. Nearly half of MD single units (46.4%) showed the firing rate
inhibition at times of SPW-R occurrence. Moreover, about 37% (26 of 70) of this MD population
decreased their firing at least ~1s prior the SPW-R onset. Similar dynamics was observed for MD
multiunit activity and gamma-power during rat spontaneous behavior. Our results suggest that
MD inhibition plays a permissive role for initiating SPW-R-associated information transfer
underlying ‘off-line’ memory consolidation.
The study was funded by the Max Planck Society.
(1) Max Planck Institute for Biological Cybernetics - Tuebingen - Germany | (2) Centre for Imaging
Sciences - Biomedical Imaging Institute - The University of Manchester - Manchester - United Kingdom
[email protected]
Yang Mingyu | [email protected]
INDIVIDUAL DIFFERENCES IN STRESS EFFECTS ON THE ENGAGEMENT OF
MULTIPLE MEMORY SYSTEMS: THE ROLE OF GENETIC VARIATIONS
Wirz, Lisa (1) | Wacker, Jan (1) | Schwabe, Lars (1)
Stress may modulate the engagement of multiple memory systems in a manner that favors
dorsal striatum-dependent procedural over hippocampus-dependent declarative memory.
However, not all individuals are susceptible to this stress-induced shift. Despite the clinical
implications associated with these individual differences, the factors that make people
vulnerable to the stress-induced bias towards striatal memory remain elusive. In the current
study we examined genetic variants and personality traits as potential sources of these
individual differences. For this purpose, 252 healthy participants who were genotyped with
respect to several adrenergic and other stress-related polymorphisms, underwent a stressor or
a control manipulation, before they performed a probabilistic classification task that can be
supported both by the hippocampus and the dorsal striatum. To examine the neural mechanisms
associated with these individual differences, event-related potentials (ERPs) were recorded
during task performance. A deletion variant of the gene encoding the α2b-adrenergic receptor
(ADRA2B) was of particular interest, because this polymorphism is related to increased
noradrenergic activation in the amygdala following arousal or stress and the amygdala is
thought to mediate the stress-induced shift from hippocampal to striatal memory. We expect
that compared to non-carriers ADRA2B deletion carriers shift significantly more often to the
procedural memory system after stress. At the neural level, earlier ERP components that likely
reflect procedural memory processes are expected to be more pronounced in deletion carriers,
whereas later ERPs such as the P300 that are involved in explicit memory processes are
expected to be less prominent. The data are currently being analyzed and will be presented at
the conference.
(1) Department of Cognitive Psychology - Institute for Psychology - University of Hamburg
Wirz Lisa | [email protected]
AN FMRI STUDY OF DISEMBODIMENT IN ADOLESCENT INTERNET ADDICTS
Son, Jung-Woo (1) | Kim, Yeoung-Rang (1)
Objective: When controlling a internet game character, we see our own movement performed
by an agent which is physically separated from our body. But, we consider the agent to be
ourself. 'Disembodiment' is the cognitive mechanism under which the properties of the self are
projected away from the boundaries of one's own body towards an external entity. The aim of
this study was to investigate the difference of brain activation between adolescent internet
addicts and normal controls during disembodiment - related state.
Metheod: The fMRI images were taken while the adolescent internet addiction group (N=17)
and the control group (N=17) were asked to perform the task composed with ball-throwing
animations. The task reflected on either self agency about ball-throwing or location of a ball.
And each block was shown with either different (Changing View) or same animations (Fixed
View). The disembodiment-related condition was the interaction between Agency Task and
Changing View.
Result: Within-group analyses revealed that the addiction group exhibited higher
activation in the thalamus, bilateral precentral area, bilateral middle frontal area and the area
around the right temporo-parietal junction. And between-group analyses showed that the
addiction group exhibited higher activation in the area near the left temporo-parieto-occipital
junction, right parahippocampal area, and other areas than the control group. Finally, the
duration of internet use was significantly correlated with the activity of posterior area of left
middle temporal gyrus in the addiction group.
Conclusion: Our study shows that the brain of adolescent internet addicts are more easily
activated in parieto - temporal junction, frontal area during disembodiment - related condition.
This finding suggest that adolescent internet addicts are more easily disembodied.
(1) Department of Neuropsychiatry - College of Medicine - Chungbuk National University
Son Jung-Woo | [email protected]
c-Fos EXPRESSION CORRELATES WITH PERFORMANCE IN NOVEL OBJECT
AND NOVEL PLACE RECOGNITION TASKS
Mendez, Marta (1) | Arias, Natalia (2) | Arias, Jorge, L (1)
In rodents, many studies have been carried out using novelty-preference paradigms. They agree
in that the perirhinal cortex and the hippocampus are involved in the recognition of a novel
object, “what”, and its new position, “where”, respectively. We employed these two variants
of a novelty-preference paradigm to assess if the expression of the immediate-early gene, cfos, in the dorsal hippocampus and perirhinal cortex correlates with performance,
discrimination ratio (d2), in the respective versions of the novelty preference tasks. A control
group (CO) was added to explore c-Fos activation not specific to recognition. We used 24 adult
male Wistar rats. The animals were randomly distributed into two versions of the spontaneous
object recognition paradigm: one-trial object recognition (What Group, n=8), one-trial objectplace recognition (Where Group, n=8), and a control group (CO group, n=8). The results showed
different patterns of c-Fos protein expression in the hippocampus and perirhinal cortex. The
Where Group presented more c-Fos positive nuclei than What and CO groups in CA1 and CA3
regions, whereas in the perirhinal cortex, the What Group showed more c-Fos positive nuclei
than Where and CO groups. The results of correlations indicate that levels of c-Fos in CA1 area
and perirhinal cortex correlate with effective exploration, d2, on the respective versions of the
novelty preference tasks, novel place and novel object recognition. However, it is important
to take into account that these are correlation findings which do not imply causal relation
between c-Fos expression and behaviour.
This research was supported by Project Grants of the Spanish Ministry of Economy and
Competitiveness: PSI2010-19348 and PSI2013-45924-P.
(1) Department of Psychology and INEUROPA - University of Oviedo Spain
Mendez Marta | [email protected]
DOPAMINE D1 RECEPTOR STIMULATION IMPAIRS ENCODING AND
RETRIEVAL IN A NOVEL OBJECT RECOGNITION TASK: ROLE OF THE
PRELIMBIC CORTEX
Marshall, Hayley, J (1) | Pezze, Marie, A (1) | Fone, Kevin, C (1) | Cassaday, Helen, J (1)
Dopamine D1 receptor antagonists have been reported to impair novel object recognition (NOR)
memory. However, the effects of dopamine D1 receptor agonists have yet to be established.
This present study examined the effects of the selective dopamine D1 receptor agonist
SKF81297 on encoding and retrieval in the NOR task in male Wistar rats. SKF81297 (0.4 and
0.8mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition,
irrespective of whether this was tested 10 min or 24h later. The same drug treatments given
15 min before the choice test stage, similarly reduced NOR memory tested 24h after the sample
phase. Thus these data suggest that D1 receptor stimulation modulates both the encoding and
retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into
the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the
sampling phase also impaired performance in the NOR task.
There is independent evidence that systemic administration of DA D1 receptor agonists
increases locomotor activity and some effects on sample exploration were also seen in the
present experiments. However the pattern of deficits in NOR was for the most part clearly
distinguishable from more general effects on object exploration.
We therefore conclude that DA D1 receptor activation impairs both encoding and retrieval in
the NOR task. In addition, the results demonstrate that D1 receptor transmission within the
prelimbic sub-region of the mPFC is important for NOR memory. These effects of prefrontal D1
receptor stimulation resemble those reported following mPFC D1 receptor antagonism in
previous studies. Taken together, these findings suggest that NOR requires an optimal level of
D1 receptor stimulation in the mPFC.
This work was supported by the BBSRC (ref. BB/K004980/1).
(1) University of Nottingham UK
Marshall Hayley J | [email protected]
EFFECTS OF MUSCIMOL-INDUCED INACTIVATION AND DOPAMINE D1
MODULATION IN THE ANTERIOR CINGULATE CORTEX ON TRACE
CONDITIONING IN A CER PROCEDURE
Cassaday, Helen, J (1) | Marshall, Hayley, J (1) | Pezze, Marie, A (1)
Trace conditioning has previously been reported to be impaired by lesions in the anterior
cingulate (AC) sub-region of the medial prefrontal cortex (mPFC). Reversible inactivation
provides a more selective technique to examine the role of AC in that there is insufficient time
for compensatory changes to develop and the inactivation can be restricted to the conditioning
stage of the procedure. Since dopamine (DA) is a key modulator of mPFC function, the
administration of DA receptor agents should provide an alternative method to test the role of
AC in trace conditioning.
In two experiments, a 5s conditioned stimulus (CS, noise) was followed by an unconditioned
stimulus (US, shock) with or without a 10s trace interval interposed between these events in a
between-subjects design. Conditioned suppression of drinking was subsequently measured as
lick suppression in response to the CS or an experimental background stimulus (flashing lights,
previously presented for the duration of the conditioning session). In Experiment 1, either a
low (62.5µg/side) or a high dose (125µg/side) of the GABAA receptor agonist muscimol was
administered by intra-cerebral microinfusion directly into AC. In Experiment 2, the selective
DA D1 agonist SKF81297 (0.05 µg/side) or DA D1 antagonist SCH23390 (0.5 µg/side) was
administered directly into AC at the same coordinates. It was predicted that these
manipulations should be sufficient to impair trace (but not delay) conditioning.
When tested for conditioning to the CS, the trace conditioned (10s) groups showed less learning
than the control conditioned (0s) groups. Counter to prediction, there was no difference in
trace conditioning between the infusion groups in either experiment. However, there was
nonetheless some indication of behavioural effects of both SKF81297 and muscimol infusions,
on suppression to the contextual cues provided by the experimental background stimulus.
This work was supported by the BBSRC (ref. BB/K004980/1).
(1) University of Nottingham UK
[email protected]
Cassaday Helen J | [email protected]
THE ROLE OF THE MEDIAL PREFRONTAL CORTEX IN EXTINCTION OF
RECENT AND REMOTE CONDITIONED ODOR AVERSION AND FEAR
CONDITIONING IN JUVENILE AND ADULT ANIMALS
Awad, Walaa (1) | Maroun, Mouna (1) | Ferreira, Guillaume (1)
Contextual fear conditioning (CFC) and conditioned odor aversion (COA) are behavioral
paradigms based on associations between neutral conditioned stimuli (CS) with aversive
unconditioned stimuli (US). In fear conditioning, the infralimbic subregion of the medial
prefrontal cortex (IL-mPFC) was intensively reported to have a key role in consolidation or
recall of recent fear extinction memory. We recently provided evidence that the IL is similarly
required for extinction consolidation of recent (24 hrs) and remote (28 days) fear memory.
However, in COA, the IL was only involved in extinction consolidation of recent, but not remote
memory (Awad et al., 2015 NPP). Based on our recent findings that post-weanling (PW) animals
have different mechanisms of extinction than the adult animals (Schayek and Maroun, Biological
Psychiatry, 2014), in this study we further explored the role of the IL in recent and remote CFC
and COA in the PW animal.
To that end we evaluated the effects of Lidocaine (reversible inactivation) or Anisomysin
(protein synthesis inhibitor) microinjection into the IL-mPFC 24 hours or 28 days after COA/CFC
acquisition in the PW animals. Our results show that the IL plays a differential role in extinction
of CFC and COA. Namely, while the CFC extinction seems to require intact IL-mPFC, COA
extinction is IL-mPFC independent.
These results may suggest that during the transition from juvenility to adulthood the IL of the
mPFC takes generalized role in mediating extinction of various types of aversive memories
(Awad et al., 2015; Akirav et al., 2006).
(1) University of Haifa - Israel
Awad Walaa | [email protected]
TARGETING BRAIN RHO GTPASES IN RETT SYNDROME: PRECLINICAL
EVIDENCE OF THERAPEUTIC EFFECTS
De Filippis, Bianca (1) | Ricceri, Laura (2) | Laviola, Giovanni (1)
Rho GTPases are a group of proteins with a well-established role as regulators of actin
cytoskeleton dynamics in response to extracellular stimuli.
Consistent with their involvement in neurobiological processes related to cognition and synaptic
plasticity, mutations in genes encoding for several regulators and effectors of the Rho GTPases
underlie various forms of intellectual disabilities (ID).
Based on this evidence, in the last few years we have investigated whether the activation of
brain Rho GTPases rescues the neurobehavioral phenotype in a mouse model of Rett syndrome
(RTT), a rare neurodevelopmental disorder and a genetic cause of ID.
Our first approach consisted of a single intracerebroventricular injection of CNF1, a bacterial
protein produced by several strains of Escherichia coli, able to enter cells and to specifically
activate the Rho GTPases Rho, Rac and Cdc42. We found that RTT-related phenotypic and
molecular alterations as well as brain mitochondrial dysfunction can be rescued by modulation
of Rho GTPases by CNF1. Recently, we have extended these findings by demonstrating the
activation of Rho GTPases in mouse brain by intraperitoneal administration of LP-211, a
selective and brain penetrant serotonin receptor 7 agonist.
This treatment restores behavioural and synaptic plasticity deficits and rescues molecular
alterations in the brain of a RTT mouse model.
These results pave the way to innovative therapeutic approaches for RTT targeting brain
RhoGTPases.
(1) Behavioural Neuroscience Section - Dept. Cell Biology & Neuroscience - Istituto Superiore di Sanita'
- Italy | (2) Neurotoxicology and Neuroendocrinology Section - Dept. Cell Biology & Neuroscience Istituto Superiore di Sanita' - Italy
De Filippis Bianca | [email protected]
DEFICIENT PURPOSEFUL USE OF FOREPAWS IN FEMALE MICE MODELLING
RETT SYNDROME
De Filippis, Bianca (1) | Musto, Mattia (1) | Altabella, Luisa (2) | Romano, Emilia (1) |
Canese, Rossella (2) | Laviola, Giovanni (1)
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe
behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene
(MECP2) cause more than 95% of classic cases. Motor abnormalities represent a significant part
of the spectrum of symptoms affecting RTT patients and are the cause of a marked decreasing
in the quality of their life. In the present study we investigated motor coordination and fine
motor skill domains in MeCP2-308 mice, a validated RTT model. This was complemented by the
in vivo magnetic resonance spectroscopy (MRS) analysis of metabolic profile in behaviourallyrelevant brain areas. We focused our investigation on females, the most affected gender in RTT.
MeCP2-308 heterozygous female mice (10-12 months of age) were impaired in tasks validated
for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini
handling task). A fine-grain analysis of spontaneous behaviour in the home-cage also revealed
an abnormal handling pattern when interacting with the nesting material, reduced motivation
to explore the environment and increased time devoted to feeding in RTT mice. The brain MRS
in vivo evaluation highlighted decreased levels of bioenergetic metabolites such as creatine and
taurine in the striatal area in MeCP2-308 female mice compared to controls. Present results
confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify
novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be
tested.
(1) Behavioural Neuroscience Section - Dept. Cell Biology & Neuroscience - Istituto Superiore di Sanita'
- Italy | (2) Molecular and Cellular Imaging Section - Dept. Cell Biology and Neuroscience - Istituto
Superiore di Sanita'- Italy
De Filippis Bianca | [email protected]
ACTIVATION AND POSITIVE ALLOSTERIC MODULATION OF ALPHA 7
NICOTINIC ACETYLCHOLINE RECEPTORS REVERSE KETAMINE-INDUCED
COGNITIVE INFLEXIBILITY IN RATS
Nikiforuk, Agnieszka (1) | Potasiewicz, Agnieszka (1) | Popik, Piotr (1)
Alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) play important roles in the regulation of
cognitive functions. Moreover, it has been suggested that α7-nAChRs might be implicated in the
pathophysiology of schizophrenia. Thus, α7-nAChRs have generated great interest as targets of
new pharmacological treatments for cognitive dysfunctions in schizophrenia. The activity of
α7-nAChR can be modulated through either orthosteric agonists or positive allosteric
modulators (PAMs). It has been suggested that α7-nAChR PAMs may offer several advantages
over the direct agonist approach.
Therefore, the aim of the present study was to evaluate the efficacies of the α7-nAChRs agonist
and PAM, A-582941 and PNU-120596, respectively, against ketamine-induced cognitive
inflexibility as assessed in the attentional set-shifting task (ASST) in rats.
Our results revealed that ketamine significantly and specifically impaired the performance of
rats at the extra-dimensional shift stage of the ASST, indicated as an increased number of trials
to criterion during this phase. The acute administration of A-582941 (1 mg/kg) and PNU-120596
(1 mg/kg) reversed the ketamine-induced cognitive inflexibility. Methyllycaconitine, a selective
α7-nAChR antagonist, fully blocked the procognitive effects mediated by A-582941 and PNU120596, suggesting that the procognitive effects of these compounds are α7-nAChRs-dependent.
The ligands of α7-nAChRs demonstrate preclinical efficacy against the schizophrenia-like
cognitive impairment. The procognitive efficacy of the α7-nAChR PAM is comparable to this of
the orthosteric agonist. Therefore, the use of α7-nAChR PAMs as a potential treatment strategy
in schizophrenia is supported.
This study was supported by the NCN grant 2012/07/B/NZ7/01150.
(1) Institute of Pharmacology - Polish Academy of Sciences - Poland
Nikiforuk Agnieszka | [email protected]
NEUROCHEMICAL AND BEHAVIORAL IMPAIRMENT OF MICE WITH HIGH AND
LOW IMMOBILITY TIME AFTER RESTRAINT STRESS
Reis-Silva, Thiago, M (1) | Lima, Ana Paula, N (1) | Moreira, Natalia (1) | Calefi, Atilio, S (1)
| Sandini, Thaísa, M (1) | Florio, Jorge Camilo (1) | Bernardi, Maria Martha (2)
High and low immobility on the tail suspension test is a common tool for assessing
antidepressant drugs effects. However, those parameters might be a natural phenotype present
in the mice population and could be selected through behavior evaluation without an induceddrug behavior need. High immobility has been also related to depressed-like behavior, that in
humans are characterized by wide range of symptoms, such as anhedonia, anxiety and tiredness.
For this study, mice with high and low immobility time were selected on the tail suspension
paradigm (Bioethical protocol #3925110614) and then tested on different behavioral essays
before and after a 2h restraint stress during a three days protocol. Thereafter, the animals
were euthanized and their brains were collected for analysis of neurochemical profile. The
results shows that mice with high and low immobility time differ in the sucrose consumption
after 72h of evaluation (P = 0.0127) but shows no differences after the restraint stress (P =
0.8930). Differences were also observed in the time spent in dark zone after restraint stress on
the dark/light box test (P = 0.0212). Our neurochemical results show a low concentration of
serotonin (P <= 0.0001), norepinephrine (P = 0.0005) and dopamine metabolite HVA (P <=
0.0001) on hypothalamus in the high vs low immobility time mice after restraint stress. The
5HIAA/serotonin turn-over (P = 0.0161), as well as the HVA/dopamine turn-over (P = 0.0072)
also showed differences between the different immobility profiles after stress. These results
demonstrate that the different behavioral profiles accessed through behavior selection on the
tail suspension test respond differently on behavior before and after restraint stress and that
the neurotransmitter profile between them are different and compatible with the impairment
observed in depressed-like behavior.
(1) University of Sao Paulo - Brazil | (2) Paulista University - Brazil
Reis-Silva Thiago M | [email protected]
EFFECTS OF DAILY SANSHO INTAKE ON THE ILEUM ACTIVITIES IN STRESSLOADED RATS
Kimoto, Mari (1) | Zeredo, Jorge, L (2) | Yamashita, Hiromi (3) | Kaida, Kei (3) | Ota,
Masato, S (1) | Nihei, Zenro (3) | Toda, Kazuo (3)
Objective: Sansho (Japanese pepper) is a common spice widely used in Japanese cuisine. It is
also an important component in Kampo preparations, such as “Daiken Chuto”, which stimulates
gastrointestinal motility and improves postoperative symptoms in the ileus. On the other hand,
we previously reported that gravity-stress produces negative effects on ileal movements.
Therefore, in the present study, we examined changes in ileal motility after gravity stress with
and without Sansho intake in male and female rats.
Methods: Rats of both sexes (Wistar, SPF) received either standard rat chow (control group) or
rat chow with 0.5% Sansho powder (SAN group). 3G stress (every day for 10 min) was loaded by
a centrifugal apparatus for 30 days in all animals. Immediately after the stress loading at day 1
(short-) and day 30 (long-term), a 1 cm-long section of the ileum was isolated under barbiturate
anesthesia and fixed in a Magnus-type chamber filled with Tyrode solution. Ileal movements
were activated by topical Acetylcholine (Ach,10-5 mg/ml) application and maximum amplitudes
(MA) of the evoked contraction were recorded.
Results: Clear tonic patterns were observed in the ileal motility after Ach application. After
short-term stress, there were no significant differences in MA between control and SAN groups
in both sexes. However, after long-term stress, significant enhancement of MA was observed in
SAN group in males, but not in females.
Conclusions: The present study showed that SAN affected Ach-induced tonic ileal motility in
male, but not in the female rats after long-term stress loading, indicating sex differences in
the effects of Sansho intake. It is suggested that Sansho may be more effective in males than
in females in reducing negative stress responses.
(1) Japan Women's University -Japan | (2) University of Brasilia -Brasil | (3) Nagasaki UniversityJapan
Kimoto Mari | [email protected]
HIPPOCAMPUS AS A MEDIATOR OF CONTEXTUAL CHANGES: FEAR
CONDITIONING ASSESSMENT
Arias, Natalia (1) | Méndez, Marta (2) | Arias, Jorge, L (2)
The importance of the context has been broadly studied in the management of phobias and in
the drug addiction literature. The way in which changes to a context influence behavior after
the simple acquisition of a passive avoidance task remains unclear. The hippocampus has long
been implicated in the contextual and spatial processing required for contextual fear, but its
role in encoding the aversive component of a contextual fear memory is still inconclusive. Our
work tries to elucidate whether a change in context, represented as differences in the load of
the stimuli, is critical for learning about the context-shock association and whether this
manipulation of the context could be linked to any change in metabolic brain activity
requirements. For this purpose, we used an avoidance conditioning task. Animals were divided
into three different experimental conditions. In one group, acquisition was performed in an
enriched stimuli environment and retention was performed in a typically lit chamber (the PAACQ-CONTX group). In another group, acquisition was performed in the typically lit chamber
and retention was undertaken in the highly enriched chamber (the PA-RET-CONTX group).
Finally, for the control group, PA-CN-CONTX, acquisition, and retention were performed in the
enriched stimuli environment. Our results showed that the PA-ACQ-CONTX group had longer
escape latencies and poorer retention than the PA-RET-CONTX and PA-CN-CONTX groups after
24 h of acquisition under contextual changes. To study metabolic brain activity, histochemical
labelling of cytochrome c-oxidase (CO) was performed. CO results suggested a neural circuit
including the hippocampus, amygdala, thalamus, parahippocampal cortices and mammillary
nuclei that is involved in the learning and memory processes that enable context-dependent
behavior. These results highlight how dysfunction in this network may be involved in the
contextualization of fear associations that underlie several forms of psychopathology, including
post-traumatic stress disorder, schizophrenia and substance abuse disorders.
(1) University if Cambridge-UK | (2) University of Oviedo
Arias Natalia | [email protected]
ELEMENTARY MOTION CUES TO ANIMACY RECOGNITION: SOCIAL
PREFERENCES FOR ACCELERATING OBJECTS IN NAIVE DOMESTIC CHICKS
(GALLUS GALLUS DOMESTICUS)
Orsola, Rosa Salva (1) | Lorenzi, Elena (1) | Grassi, Massimo (2) | Regolin, Lucia (2) |
Vallortigara, Giorgio (1)
Motion cues, implying the presence of an internal energy source, elicit animacy perception in
adults and preferential attention in infants. We investigated whether speed changes affecting
adults’ animacy ratings elicit spontaneous social preferences in visually-naïve chicks. Twenty
adult human observers evaluated the similarity between the movement of a red blob and that
of an animate living creature. The red blob entered the screen and moved along the azimut.
Halfway through its trajectory the object could either continue to move at a constant speed
and direction, or reverse its motion direction and/or linearly increase its speed. The average
speed, the distance covered by the object and the overall motion duration were kept constant
across stimuli. Subjects reported significantly higher animacy ratings for accelerating objects,
regardless of whether they reverted their motion direction. Two-day-old chicks were tested for
their spontaneous preference for approaching the red object moving at a constant speed and
trajectory (inanimate stimulus) or an identical object, which suddenly accelerated and then
decelerated again to the original speed (animate stimulus). Chicks showed a significant
preference for the animate stimulus, indicating that motion cues causing animacy perception
in humans elicit spontaneous preferences in naïve animals.
(1) CIMeC University of Trento - Italy | (2) DPG University of Padova - Italy
Orsola Rosa Salva | [email protected]
VHUMAN-LIKE PERCEPTION OF THE EBBINGHAUS ILLUSION IN TWO
DISTANT SPECIES: DOMESTIC CHICKS AND REDTAIL SPLITFINS
Orsola, Rosa Salva (1) | Albertazzi, Liliana (1) | Cavazzana, Annachiara (2) | Regolin, Lucia
(2) | Rugani, Rosa (1) | Sovrano, Valeria, A (1)
In the Ebbinghaus illusion, a central circle surrounded by small circles (inducers) appears bigger
than an identical one surrounded by large inducers. Three previous studies failed to
demonstrate sensitivity to this illusion in bantams chickens, pigeons and baboons, suggesting
that other animals might lack the neural substrate necessary to perceive the Ebbinghaus illusion
in a human-like fashion. Using procedures that do not force the animals to look at stimuli from
a close distance, allowing them to take in their global configuration, we were show that his
illusion is perceived by 4-day-old domestic chicks (Gallus gallus domesticus) and by a fish of the
Goodeidae family (redtail splitfin, Xenotoca eiseni). Animals were trained to recognize the
reward location with either a big or a small orange circle (grey circles of different dimensions
were present at both rewarded and unrewarded locations). When tested with the illusory
configurations (two same-sized orange circles surrounded one by big gray inducers, the other
by small gray inducers), animals reinforced on the small target choose the configuration with
big inducers, in which the central target appears perceptually smaller; the opposite was true
for subjects reinforced on the big target. Thus, animals chose the stimulus that, on the basis
of a perception of the Ebbinghaus illusion, appeared deceptively larger or smaller, consistent
with the condition of training. These results have important implications for the evolutionary
history of the neural substrate involved in the perception of the Ebbinghaus illusion.
(1) CIMeC University of Trento - Italy | (2) DPG University of Padova
Orsola Rosa Salva | [email protected]
SOCIAL THREAT EXPOSURE IN JUVENILITY PROMOTES RELAPSE TO
COCAINE SEEKING BY ALTERING BLOOD CLOTTING AND BRAIN
VASCULATURE
Carola, Valeria (1) | Lo Iacono, Luisa (1) | Valzania, Alessandro (1) | Visco-Comandini,
Federica (2) | Aricò, Eleonora (3) | Castiello, Luciano (3) | Viscomi, Maria Teresa (1) |
Puglisi-Allegra, Stefano (1)
Childhood maltreatment is associated with increased severity of substance use disorder (SUD).
However, the molecular and neurobiological substrates engaged during early traumatic events
and mediating the increased relapse risk are poorly understood. To open perspective on new
therapeutic targets and prevention of substance use disorder (SUD) and relapse a deeper
understanding of these phenomena is crucially required. Recently, we have shown that the
exposure to a threatening social experience in juvenile mice (social stressed, S-S) influences
the propensity to reinstate cocaine seeking after withdrawal periods. Being the possibility of
preventing relapse, using biomarkers measurable in non-invasive manner, considered a major
clinical “advancement” in the treatment of addiction, we decided to investigate the blood gene
expression changes associated with the increased reinstatement susceptibility of the S-S mice.
A genome wide analysis was performed on RNA extracted from Peripheral Blood Mononuclear
Cells of S-S and control mice in cocaine withdrawal. This analysis revealed that more than 1000
transcripts, enriched in the classes of blood coagulation and integrin signaling, were upregulated in S-S group compared to controls. Furthermore, the increased blood coagulation
performance in S-S mice was associated with a strong pauperization of brain microvasculature.
In light of these evidences, we decided to apply a treatment with an anticoagulant agent to
ameliorate the blood circulation in these mice. Interestingly, this treatment was able to abolish
the susceptibility to reinstate cocaine seeking in S-S mice. These findings uncover a molecular
mechanism that might contribute to into cocaine abuse observed in individuals who had
experienced childhood maltreatment.
(1) IRCSS Fondazione Santa Lucia - Italy | (2) University of Rome La Sapienza - Italy | (3) Istituto
Superiore di Sanità - Italy
| [email protected]
Carola Valeria | [email protected]
THE EFFECT OF KETAMINE AND MK-801 ON RECONSOLIDATION OF FOOD
INSTRUMENTAL MEMORY WHEN GIVEN UNDER A ‘METAPLASTICITY’
PROTOCOL
Piva, Alessandro (1) | Gerace, Elisabetta (2) | Di Chio, Marzia (1) | Armani, Federica (1) |
Tedesco, Vincenzo (1) | Pellegrini, Giampietro Domenico (2) | Chiamulera, Cristiano (1)
Reconsolidation is the mechanism that restores previously consolidated memory traces after
their reactivation induced by re-exposure to environment or stimuli. Memory reactivation
induces destabilization, a labile phase during which synapses can be enhanced or weakened,
resulting in memory restabilization or disruption. NMDA receptors, and more precisely GluN2B
and GluN2A, were shown to modulate respectively the destabilization and restabilization of
previously consolidated memories. These receptors are also known to be involved in
metaplasticity, i.e., potentiation of neuroplasticity phenomena.
The aim of our study was to investigate the effect of NMDA channel blockers on destabilization
and reconsolidation of food instrumental memories when given under a protocol of
administration known to induce ‘metaplasticity’. Therefore, we tested whether NMDA blockers
MK-801 or ketamine given one day prior to food instrumental memory retrieval may reduce
reinstatement of food-seeking behaviour in rats previously trained to food self-administration.
After a period of forced abstinence, intraperitoneal 4 mg/kg MK-801 or intravenous 10 mg/kg
ketamine were given to rats 24 hours before the re-exposure to training context and to lever
responding, up to a maximum of 20 lever pressing without contingency. MK-801, but not
ketamine, inhibited reinstatement compared to vehicle and control groups treated with MK801 or ketamine but without retrieval.
To investigate the molecular changes induced by MK-801 or ketamine injection, we also
analysed the pattern of expression of different glutamatergic receptors in specific rat brain
areas involved in memory processes. Interestingly, preliminary western blot data showed that
the level of GluN2B subunit-containing NMDA receptor expression in amygdala was significantly
decreased 24 hours after the treatment with intraperitoneal 4 mg/kg MK-801 but not with
intravenous 10 mg/kg ketamine.
We suggest that previous day treatment with MK-801, but not ketamine, reduces the
reinstatement of food-seeking behaviour through a GluN2B-NMDA-dependent inhibition of
instrumental memory reconsolidation.
(1) Univ Verona - Italy | (2) Univ Florence - Italy
Piva Alessandro | [email protected]
DIFFERENT MODULATION OF KETAMINE-INDUCED NEUROPLASTICITY BY
ACUTE OR CHRONIC SELF-ADMINISTRATION: DISSECTING THE
ANTIDEPRESSANT VS. REINFORCING EFFECTS IN THE RAT BRAIN
Di Chio, Marzia (1) | Caffino, Lucia (2) | Giannotti, Giuseppe (2) | Venniro, Marco (1) |
Mutti, Anna (1) | Padovani, Laura (1) | Cheung, David (3) | Fumagalli, Guido (1) | Yew,
David, T (3) | Fumagalli, Fabio (2) | Chiamulera, Cristiano (1)
Neuroadaptive changes such as expression of Zif-268 and release of BDNFare observed
respectively after drug self-administration and antidepressants treatment. Ketamine owns both
reinforcing properties (i.e., to maintain chronic self-administration) and anti-depressant
effects (on a single infusion regimen). Theobjective of this study was to assess Zif-268 and BDNF
in rat brain after single or self-administered ketamine in rats, with the aim to discriminate
between its reinforcing and antidepressant molecular effects.
Rats were exposed to self-administerintravenous (IV) ketamine (S/A) for 30 days (average daily
intake 6.4 ± 2.7 mg/kg (mean ± SD), or to receive a single IV ketamine 0.5 mg/kg (Single) or
vehicle infusion. Brains were perfused and processed for immunohistochemistry against Zif-268
in prefrontal cortex (PFC), ventral striatum (VS), ventral tegmental area (VTA), hippocampus
(H), and basolateral amygdala (BL). BDNF protein levels in VS and H were assessedby Western
blotting.
A significant main effect of ketamine on Zif-268 expression was seen in VS, H and BL.
However,S/A rats showed a significant increase of Zif-268 only in VS and BL vs. vehicle, with
no changes in VTA. On the other hand, a significant decrease of Zif-268 vs.vehicle was measured
for both S/A and Single groups in H.
BDNF levels in H were significantly increased in Singlevs. vehicle, whereas S/A group showed a
decrease. In VS, we observed a significant decrease of BDNF in both groups vs. vehicle. These
changes in BDNF were mirrored by similar changes in TrkB.
We showed differences in Zif-268 and BDNF expression after S/A or single ketamine infusion
that are similarly induced by addictiveorby antidepressant drugs. These differencessuggest a
clear molecular discrimination between reinforcing and antidepressant dose-regimes effects of
ketamine.
 
(1) UniVr-Italy | (2) UniMi-Italy | (3) University of Hong Kong-Hong Kong
Di Chio Marzia | [email protected]
VENTRAL PALLIDUM AND CUE-DRIVEN REWARD SEEKING: NEURAL
ENCODING AND NEUROCHEMICAL INPUTS
Richard, Jocelyn, M (1) | Fields, Howard, L (2)
The ventral pallidum (VP) is critical for seeking natural and drug rewards. Neural activity in the
VP encodes the value of both primary rewards and reward-related, or incentive, cues. Here,
we investigated the relationship between VP encoding of incentive cues and reward-seeking
actions generated in response to those cues. Additionally, we explored the neurochemical
inputs to VP that contribute to behavioral responses elicited by these incentive cues. Rats were
trained to perform a discriminative stimulus (DS) task in which lever presses after one auditory
cue (the DS or incentive cue) result in presentation of sucrose reward, whereas lever presses
after another auditory cue (the non-predictive stimulus; NS) have no consequences. The
majority of neurons were excited by the DS to a much greater extent than by the NS.
Importantly, we also found a significant relationship between the firing rate of many of these
excited neurons and the animal’s latency to make a behavioral response following the DS,
suggesting these excitations may play a causal role in cue-induced reward seeking actions.
Consistent with this idea, inactivation of VP with the GABA agonists baclofen and muscimol
significantly reduced cue-induced reward-seeking, but did not affect overall reward-seeking,
or reward-seeking following the control cue. These results suggest that excitatory responses in
VP neurons promote the vigor of cue-driven reward seeking. In contrast, non-selective
dopamine blockade of VP with flupenthixol reduced responding in a manner that was not cuespecific, suggesting that dopamine inputs may be important for enabling responding more
generally. Finally, blockade of substance P's actions in VP, with infusion of an NK-1 antagonist,
had no effect on reward-seeking, suggesting that substance P inputs from nucleus accumbens
are not a critical contributor to cue-driven reward seeking in this task.
(1) Johns Hopkins University - USA | (2) University of California
Richard Jocelyn M | [email protected]
COGNITIVE IMPAIRMENT IN A MURINE MODEL OF EXPERIMENTAL
AUTOIMMUNE ENCEPHALOMYELITIS WITH RELAPSING-REMITTING COURSE
Rosell del Valle, Cristina (1) | Sánchez Morales, Cristina (1) | Gómez-Conde, Ana Isabel (2) |
Hurtado Guerrero, Isaac (2) | Fernández Fernández, Oscar (2) | Pedraza Benítez, Carmen (1)
| Santín Nuñez, Luis Javier (1) | Estivill-Torrús, Guillermo (2)
Multiple sclerosis (MS) is a neuroinflammatory disorder characterized by demyelination and
progressive axonal loss that affects the central nervous system. In addition of physical disability
and the neurodegenerative process, MS associates with co-morbid behavioral, neuropsychiatric
and cognitive impairment, including learning and memory deficits. The study of cognitive
impairment in the currently most suitable experimental animal model of MS, experimental
autoimmune encephalomyelitis (EAE), constitutes a very valuable tool to ultimately translate
into clinical a better diagnosis and more effective treatment protocols. In our study, we
analyzed the behavioral profile of a murine model of EAE induced by myelin oligodendrocyte
glycoprotein peptide (MOG 35-55) which develops a relapsing-remitting course. In the early
neuroinflammatory phase of the disease, i.e. 19-21 days post immunization (dpi), EAE mice
exhibited deficits in motor coordination/skill learning (Rotarod test), and spatial working
memory (spontaneous alternation in Y-maze), as well as depressive symptoms (tail suspension
test) and anxiety-like behavior (elevated plus-maze). EAE mice did not yet show object
recognition memory impairments, suggesting that reference memory was not altered in this
phase. However, from 33-35 dpi until late phases (49-52 dpi), independently of clinical score,
EAE mice exhibited a memory decline showing lower discrimination index in the object
recognition test. EAE late phase was also characterized by motor coordination and spatial
working memory impairments as well as higher anxiety-like behavior. Overall, these data
demonstrates a differential pattern of gradual cognitive dysfunctions during the relapsingremitting EAE course that could help to understand the development of progressive cognitive
decline in MS patients.
Funding: Andalusian Regional Ministries of Economy, Innovation, Science and Employment (SEJ1863; CTS643) and of Health (PI-0234-2013; Nicolas Monardes Programme).
Keywords: EAE, cognitive dysfunction, memory decline.
(1) Instituto de Investigacion Biomedica de Malaga (IBIMA) - Universidad de Malaga - Spain | (2)
Instituto de Investigación Biomédica de Malaga (IBIMA) - Hospital Regional de Málaga - Spain
[email protected] | [email protected] | [email protected] | [email protected] |
[email protected]
Rosell del Valle Cristina | [email protected]
STRESS MODIFIED NOCICEPTIVE RESPONSES IN THE ANTERIOR CINGULATE
NEURONS DURING ESTROUS CYCLE IN FEMALE RATS
Yamashita, Hiromi (1) | Zeredo, Jorge, L (2) | Zenro, Nihei (1) | Kaida, Kei (1) | Kimoto,
Mari (3) | Toda, Kazuo (1)
Stress can modify various emotional system. Anterior cingulate cortex is strongly involved in
emotion related to pain in men and animals. In female, the estrous cycle is key condition that
affects emotional behavior. Therefore, in the present study, we investigated stress modified
nociceptive responses in the anterior cingulate neurons during estrous cycle in female rats
Methods:
Wistar albino rats (bw: 130-146 g) were used. Animals were kept in a temperature-controlled
room (24 ± IºC) under a 12:12 light/dark cycle (light on from 0700 to 1900 hr). Six hours/day of
stress was applied using metal mesh-restraint for 3, 7 and 21 days. The rat estrous cycle is
usually divided into four phases: proestrous, estrous, metestrous and diestrous. The phases of
the rat estrous cycle were determined from vaginal smears with Giemsa-stain using low-power
light microscopy. Noxious pinch stimuli were applied on three body sites (nose, back and tail).
Neuronal activities were recorded from single neurons in the cingulate cortex. The firing
frequency of neurons before and after 5s-pinch stimuli was compared after stress loading.
Enhancement of nociceptive responses were observed in the proestrous/estrous phase at day
of 7. No significant changes were observed in nociceptive responses during
metestrous/diestrous phase. At day of 3 and 21, no significant changes of nociceptive responses
were observed during all estrous cycles.
Conclusion:
The present results indicate that nociceptive responses in the anterior cingulate can be
modulated by stress loading. Especially, changes were clear in the proestrous/estrous phase.
(1) Nagasaki University-Japan | (2) University of Brasilia-Brasil | (3) Japan Women's University-Japan
Yamashita Hiromi | [email protected]
STRAIN- AND RESPONSE-DEPENDENT EFFECTS OF CAFFEINE ON ANXIETYRELATED BEHAVIOUR IN RATS
Hughes, Robert, N
High doses of caffeine can elicit anxiety symptoms for people who are not habitual caffeine
consumers. Although high acute doses often have anxiogenic effects in rats, there are
examples of where this is not so and may even produce anxiolysis. In a recent study involving
PVG/c rats where anxiogenesis did not occur with doses of 25 and 50 mg mg/kg of caffeine, it
was suggested that the drug’s effects might have depended on the subjects’ strain (Hughes et
al., 2014). Therefore, effects of 50 mg/kg of acute caffeine on anxiety-related behaviour in
an open field and an elevated plus maze were compared in rats of the inbred hooded PVG/c
strain, and the outbred albino Wistar strain. Caffeine led to a decrease in ambulation (distance
travelled) and rearing in the open field for Wistar rats (anxiogenesis?), but an increase in
ambulation for PVG/c rats (anxiolysis?). For both strains combined, the drug increased the time
spent walking and occupying the centre of the apparatus (anxiolysis?) but increased grooming
(anxiogenesis?). While there was no strain difference in effects on entries into and occupation
of the open arms in the elevated plus maze, for the two strains combined, both of these
measures were increased by the drug (anxiolysis?). Caffeine also decreased entries into the
enclosed arms for Wistar but not PVG/c rats, thereby eliminating the likelihood of all subjects’
open-arm behaviour being an artefact of heightened locomotor activity. Although two of
caffeine’s significant effects were strain-dependent, the other three applied equally to both
strains. It was also apparent that whether an outcome was possibly due to anxiogenesis or
anxiolysis depended upon the particular measure recorded.
University of Canterbury - New Zealand
Hughes Robert N | [email protected]
DISSOCIABLE EFFECTS OF MGLUR5 MODULATION ON MOTOR AND CHOICE
IMPULSIVITY IN RATS: INTERACTION WITH NMDA RECEPTOR ANTAGONISM
Isherwood, Sarah, N (1) | Nicholson, Janet, R (1) | Robbins, Trevor, W (2) | Dalley, Jeffrey,
W (2) | Pekcec, Anton (1)
Impulsivity describes rapid and prematurely-expressed behaviours. High levels of impulsivity
are symptomatic of several major neuropsychiatric disorders including schizophrenia,
attention-deficit hyperactivity disorder and several forms of addiction. Aberrant NMDA receptor
signalling has consistently been implicated with such brain disorders. Although synergistic
interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5),
the role of mGluR5 in modulating impulsivity is poorly understood. In this study, we investigated
the role of mGluR5 in modulating premature responding in the five-choice serial reaction time
task (5-CSRTT) and performance in a delay-discounting task (DDT) in male, Lister-hooded rats.
Additionally, we investigated the interactive role of NMDA receptors and mGluR5 in modulating
5-CSRTT performance. Following training, both unscreened rats and rats selected for high and
low levels of impulsivity were tested in the 5-CSRTT and DDT following systemic ADX47273
administration (positive allosteric mGluR5 modulator; PAM). Furthermore, the effect of
ADX47273 on a pharmacologically evoked model of impulsivity, by NMDA receptor antagonism
(MK801), was also investigated in the 5-CSRTT. ADX47273 selectively decreased premature
responding in the 5-CSRTT at doses that did not affect spontaneous locomotor activity. MK801
robustly increased premature responding and impaired attentional accuracy. These deficits
were dose-dependently attenuated by ADX47273 pre-treatment. In stark contrast, positive
allosteric mGluR5 modulation had no effect on DDT performance, despite d-amphetamine
showing efficacy. These findings demonstrate that motor and choice impulsivity, as assessed in
the 5-CSRTT and DDT respectively, are dissociable at the level of mGluR5. We further show that
positive allosteric modulation of mGluR5 may be therapeutically valuable in selectively
targeting specific aspects of impulsivity and executive dysfunction.
Complete Financial Sponsorship by Boehringer Ingelheim Pharma GmbH & Co. KG, Div. Research
Germany, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
(1) Boehringer Ingelheim - Germany | (2) Cambridge University - England
Isherwood Sarah N | [email protected]
EFFECT OF 5-HT6 RECEPTOR LIGANDS ON NEURAL NETWORK
OSCILLATIONS AND THE FIRING OF PYRAMIDAL NEURONS IN THE RAT
PREFRONTAL CORTEX IN VIVO
Brouard, Julia, T. (1) | Frisch Herrik, Kjartan (2) | Helboe, Lone (2) | De Jong, Inge, E.M. (2)
| Sharp, Trevor (1)
The prefrontal cortex (PFC) is critical for executive functions, and aberrant PFC activity may
underpin cognitive deficits that are common in dementia and neuropsychiatric disorders. 5-HT
is a key modulator of PFC activity, and the PFC is rich in 5-HT receptor subtypes, including 5HT6 receptors. Rodent studies show that 5-HT6 receptor ligands
modulate cognition but the neural substrate of this effect is currently unknown. Here we
determined the effects of the selective 5-HT6 receptor agonist WAY-181187, and
antagonist SB-399885, on neural network oscillations and the firing of individual pyramidal
neurons in the rat PFC.
Adult male Sprague Dawley rats were anaesthetised (urethane), and extracellular recordings of
the local field potential and single units were made in the PFC. Single units were identified as
pyramidal neurons on the basis of antidromic responses evoked from stimulation in the midbrain
(dorsal raphe nucleus), firing properties, or juxtacellular labelling. WAY-181187 (0.1-9 mg/kg,
i.v.) activated the PFC, causing a dose-related reduction in slow wave (SW) oscillations
compared to pre-drug levels (n=10, ANOVA p<=0.05) and a rightward shift in peak SW activity
(0.8 Hz to 1 Hz, n=10, p<=0.01, paired t-test). SB-399885 (1 mg/kg, i.v.) had no effect on SW
oscillations alone but attenuated the SW effect of WAY-181187 (p<=0.05, unpaired t-test, 0.3
mg/kg WAY181187). Single unit recordings were made from 14 PFC neurons: 6 neurons
responded to WAY-181187 (0.1-9 mg/kg) with increased firing rate, whereas 8 neurons
responded with a decrease.
In summary, the 5-HT6 receptor agonist WAY-181187 activated the PFC as evident
from reduced SW oscillations, and associated changes in pyramidal neuron firing rate.
Experiments with the 5-HT6 receptor antagonist SB-399885 suggest a role of 5HT6 receptors in this effect. This electrophysiological evidence of 5HT6 receptor modulation of PFC neural activity may be relevant to the procognitive
effects of 5-HT6 receptor ligands.
(1) Department of Pharmacology - University of Oxford - United Kingdom | (2) H. Lundbeck A/S Division of Neurodegeneration - Denmark
Email: [email protected] | | [email protected] | [email protected] |
[email protected]
Brouard Julia T. | [email protected]
SIRTUIN1 IS A CRITICAL MODULATOR OF THE EARLY TRAUMA EFFECTS ON
THE DEVELOPMENT OF DEPRESSION IN MULTIPLE SPECIES
Valzania, Alessandro (1) | Servadio, Michela (2) | Lo Iacono, Luisa (1) | Viscomi, Maria Teresa
(1) | Bisicchia, Elisa (1) | Trezza, Viviana (2) | Carola, Valeria (1)
Introduction
The correlation between early trauma and the development of depression in adulthood has
been extensively investigated in both humans and rodents. During early life, epigenetic
mechanisms are engaged to modify gene expression and brain functioning in response to
environmental inputs. Among epigenetic factors, the family of Sirtuins (SIRT) has been
implicated in mood disorders. We have recently demonstrated a critical role for SIRT1 gene in
the pathophysiology of the early trauma associated depression in both humans and mice. Here,
we aimed to investigate if a similar biological mechanism was involved in the depression-like
behavior induced by early life adversities in rats.
Methods
Rat pups were assigned to either control or Social Isolation (SI) group at postnatal day (PD) 14.
In the SI group, each rat was singly housed in a novel cage for 30’ per day from PD14 to 21. All
rats were tested for social play and depression like behavior starting from 40 days of age. After
the tests, rats were sacrificed and brain and blood were collected. Punches of striatum, nucleus
accumbens, hippocampus, and hypothalamus were obtained from brain slices. Protein content
was extracted from each sample and measured by Bradford assay. Anti-SIRT1 mouse primary
antibody was used to determine the SIRT1 protein expression levels.
Results and conclusion
When we tested the effect of the stress on social and depression-like behavior in young rats,
we observed that SI rats had a significant decrease of social exploration and an increase of
behavioral despair compared to controls. Furthermore, in SI rats this behavioral phenotype was
associated with a significant reduction of SIRT1 protein level in hippocampus, hypothalamus
and striatum. In line with our previous studies, these findings confirm SIRT1 as a modulator of
the effect of early life adversity on the development of depression in multiple species.
(1) IRCSS Fondazione Santa Lucia - Italy (2) Roma Tre University - Italy
[email protected]
Lo Iacono, Luisa | [email protected]
NEWBORN CHICKS (GALLUS GALLUS) DISCRIMINATE PROPORTIONS
Baglioni, Paolo (1) | Rugani, Rosa (2) | Vallortigara, Giorgio (2) | Regolin, Lucia (1)
A broad amount of literature shows that animals can solve numerical operations on discrete
quantities [1][2], but studies involving the discrimination of continuous quantities are sparse.
In this study we investigated the discrimination of proportions in 4-days-old chicks. During
training, chicks received food reinforcement when they approached one of two stimuli, each
characterized by different proportions of red and green areas (¼ vs. ¾). Half chicks were
trained to respond to the ¾ green area and the other half to the ¾ red area. In Experiment 1,
the spatial dispositions of the two areas were novel, in spite of this, chicks chose the correct
proportion (n=20; p<=0.001). In Experiment 2, chicks responded on the basis of proportion
(n=10; p<=0.001) even with stimuli of enlarged dimensions, which created a conflict between
the absolute positive area experienced during training and the relative proportion of the two
areas. However, chicks could have based their responses on the overall colour (red or green) of
the figures rather than proportion per se. To check for this objection, in Experiment 3, we used
new pairs of testing stimuli, each depicting a different number of squares on a white
background (i.e. 1 green and 3 red vs. 3 green and 1 red). Again, chicks chose the correct
proportion (n=10; p<=0.001), showing that they discriminated relying on the proportion of
continuous quantities, rather than the prevalent colour or the absolute amount of it. These
results indicate that chicks can track continuous quantities, suggesting that proportions are
information that can be processed by animals, even very young ones.
References
[1] Rugani, R., Fontanari, L., Simoni, E., Regolin, L. & Vallortigara, G. (2009). Proc. R. Soc.
Lond. B. 276, 2451-2460.
[2] Rugani, R., Kelly, M.D., Szelest, I., Regolin, L. and Vallortigara, G. (2010). Biol. Lett. 6:
290-292.
(1) Department of General Psychology - University of Padua - Italy | (2) Center for Mind/Brain Sciences
- University of Trento - Italy
[email protected]
Baglioni Paolo | [email protected]
LEARNING TO READ BRAILLE IN SIGHTED CHANGES SI AND SII
Kossut, Malgorzata (1) | Debowska Weronika (1)
Neuroplastic changes induced by sensory learning can affect sensory processing in the cortices
of specific modalities as well as within higher ordered multimodal areas. We examined, in a
longitudinal design, functional and structural changes induced by learning to read Braille, a
task that requires both significant tactile expertise and mapping of tactile input onto
multimodal representations. Subjects with normal vision were trained to read Braille
exclusively by touch, and scanned twice while performing a same-different discrimination task
on Braille characters. Functional and diffusion-weighted MRI were used to assess resulting
changes. The strongest training-induced effect was found in the SI cortex, where bilateral
augmentation in activity was observed. It was accompanied by an increase in white matter
integrity within the contralateral SI. In SII increased activations were not observed, but
increases of white matter fractional anisotropy were present. Changes in BOLD signal were also
found in the fusiform gyrus, the medial frontal gyri, and the inferior parietal lobule, while
increases of white matter fractional anisotropy were observed thalamus and lingual, fusiform
and parahippocampal gyri.
Braille character discrimination contrasted with a non-Braille tactile pattern revealed increased
activation in the angular gyrus, the fusiform gyrus, posterior cingulate cortex, and the middle
and inferior frontal gyri, reflecting the lexical aspect of the learning task. Our results provide
evidence for functional remodeling of the somatosensory pathway and higher order multimodal
brain areas occurring as a result of tactile learning, and add to them a novel picture of extensive
white matter plasticity.
(1) Nencki - Institute of Experimental Biology
Kossut Małgorzata | [email protected]
ADVERSE EARLY EXPERIENCES INDUCE PHYSIOLOGICAL AND FUNCTIONAL
CHANGES IN NUCLEUS ACCUMBENS OF ADULT MICE
Valzania, Alessandro (1) | Latagliata, Claudio (1) | Andolina, Diego (2) | Accoto, Alessandra
(3) | Conversi, David (3) | Puglisi-Allegra, Stefano (3) | Carola, Valeria (1)
Numerous evidences show that the risk to develop psychopathologies in adulthood is frequently
associated with exposure to trauma in childhood. The existence of such link suggests that during
development the impact of traumatic experiences on the brain induces molecular and biological
changes that may facilitate the onset of psychiatric diseases in adulthood. We have explored
the effects of the exposure to two different environmental experiences in early postnatal age
on the functionality of mouse brain. In the experimental manipulation protocols, mouse pups
were exposed to either a Social Isolation (SI) or exposure to social adverse (SA) context during
the third postnatal week. The long-term impact of these two environmental manipulations was
then evaluated in adult mouse brains. We first assessed the neuro-functional response in
nucleus accumbens, striatum and hippocampus by c-FOS immunohistochemistry. This analysis
showed not only that the exposure to stress in early ages affects this response but that different
types of stress have different impact on the developing brain. We then focus our experiments
on the nucleus accumbens, a brain structure recognized to have a central role in the reward
circuit. In vivo microdialysis experiments showed that SI and SA stress had long term effects on
the metabolism of dopamine in baseline (physiological) and in response to cocaine
administration. Finally we evaluated, by Golgi staining technique, if the exposure to stressful
conditions during early experience had long term impact on the neuronal morphology (spine
density and spine number) in this structure in adulthood. Interestingly this analysis showed that
SI and SA differently affected the neuronal morphology suggesting again that the type of stress
experienced is an important factor modulating the neuronal development. Our results showed
that a stressful experience in preadolescent age is able to induce “permanent” changes in the
mouse brain specifically in the nucleus accumbens
(1) IRCSS Fondazione Santa Lucia - Italy | (2) University of L'Aquila - Italy | (3) University of Rome La
Sapienza -Italy
[email protected]
Valzania Alessandro | [email protected]
THE EFFECT OF BRAIN ASYMMETRY ON BIOLOGICAL MOTION PERCEPTION
IN NEWBORN CHICKS (GALLUS GALLUS)
Rosa Rugani (1), Orsola Rosa Salva (1), Giorgio Vallortigara (2), Lucia Regolin (1)
A small number of light-points on the joints of a moving animal give the impression of biological
motion (BM). Visually-naive chicks prefer BM to non-BM, proving that the BM perception can be
independent from visual experience.
Interconnected regions, mainly in the right hemisphere, provide the neural substrate for BM
perception, in humans and other mammals. Evidence on the neural basis of the BM perception
in birds are lacking. In avians the information from each eye is mainly elaborated by the
contralateral hemisphere. We recorded the eye spontaneously used by chicks to observe point
light displays (PLD), to investigate brain asymmetry. We also investigated the effect of
lateralization, following light exposure of the embryos. In Experiment 1, we studied
hemispheric specialization by observing the percentage of alignment with a rightward or a
leftward walking-hen PLD. We also studied whether this could be modulated by the stimulus
orientation (upright or upside down). We found that only highly-lateralized chicks, exposed to
the upright PLD moving rightward first, aligned with the apparent direction of motion (n=72,
mean=62.100, sem=3.400;t(71)=3.603, p<0.001). Because an alignment with a rightward moving
stimulus implies monitoring it with the left-eye-system, our results suggest a right hemisphere
dominance in BM processing.
In Experiment 2 weakly-lateralized chicks did not show any behavioral asymmetry: Overall they
counter aligned with the apparent direction of motion of the upright PLD (n=161,mean=43.000,
sem=1.900; t(160)=8.622, p=0.020), suggesting a modulatory effect of brain lateralization on
social interactions. Environmental factors (light stimulation) seem to affect the development
of lateralization, and consequently social behavior.
(1) Centre for Mind Brain Sciences - University of Trento - Italy | (2) Department of General
Psychology - University of Padova - Italy
|[email protected]
Rugani, Rosa | [email protected]
WILM'S TUMOR 1, A TRANSCRIPTIONAL REGULATOR, MODULATES
MEMORY FLEXIBILITY IN MICE
Munari, Leonardo (1) | Mariottini, Chiara (1) | Gunzel, Ellen (1) | Seco, Joseph (1) | Hansen,
Jens (1) | Russo, Scott (2) | Huff, Vicki (3) | Alberini, Cristina, M (4) | Blitzer, Robert, D (1)
| Iyengar, Ravi (1)
Memories may simply vanish and decay over time due to unknown biological process. Besides
this passive process, it's been hypothesized an active form of forgetting called memory
interference, which can greatly reduce memory flexibility, although the mechanism for this
process is not understood. We identified Wilm's tumor 1 (WT1) as a key protein involved in
active forgetting. Loss-of-function WT1 transgenic mice showed enhanced hippocampal LTP,
suggesting that WT1 acts as a plasticity suppressor. These mice performed better than wild
type littermates in two hippocampus-dependent tasks: contextual fear conditioning (CFC) and
novel object placement (NOP). Interestingly, in a two-task sequential learning protocol (NOP
followed by CFC), transgenic mice showed better memory retention for NOP but impaired
learning for the subsequent CFC when tested 24 hours later, but no difference between
genotypes was seen when the tests were performed 10 days apart, suggesting a rescue of the
memory capacity. Blockade of receptors for the chemokine CCL2 and IGF2, both of which are
regulated by WT1, normalized LTP in WT1 transgenic mice, and the CCL2 receptor antagonist
suppressed memory enhancement in the NOP test. These results show that WT1, by regulating
CCL2, IGF2, and possibly other diffusible signaling molecules, actively suppresses plasticity
after learning, thereby preserving the ability of hippocampus to encode new memories and
maintaining normal memory flexibility.
Supported by NIH grants GM54508 and GM071558.
(1) Department of Pharmacology and Systems Therapeutics - Icahn School of Medicine at Mount Sinai New York, USA | (2) Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NY, USA |
(3) Department of Genetics - M.D. Anderson Cancer Center, Houston - Texas, USA | (4) Center for
Neural Science - New York University, New York, USA
Munari Leonardo | [email protected]
INTERACTION BETWEEN PRENATAL STRESS AND EXPOSURE TO HIGH-FAT
DIET AT ADULTHOOD: METABOLIC, NEUROENDOCRINE AND BEHAVIORAL
EFFECTS IN MALE AND FEMALE OFFSPRING.
Panetta, Pamela (1) | Bellisario, Veronica (1) | Capoccia, Sara (1) | Luoni, Alessia (2) |
Berry, Alessandra (1) | Riva, Marco, A (2) | Cirulli, Francesca (1)
A growing body of studies suggests that a suboptimal intrauterine environment is involved in
early programming of adult chronic diseases. In particular, maternal stress during pregnancy
can predispose the offspring to develop mood disorders and metabolic alterations later in life.
It has been suggested that both consumption of a high-fat diet (HFD) and prenatal stress (PNS)
can affect the regulation of the stress response system of an individual. Based upon previous
data, we hypothesized that PNS might work to “imprint” hypothalamic-pituitary-adrenal (HPA)
axis of the offspring, leading to a differential response to an obesogenic environment
encountered during adulthood. As we expected gender differences in response to PNS both
male and female subjects were assessed in metabolic, neuroendocrine and behavioral
alterations. In order to investigate our hypothesis pregnant Sprague-Dawley female rats
underwent a chronic procedure of restraint stress during the last week of gestation. The adult
offspring was then fed a HFD or chow diet for 4 weeks and were subsequently tested for
metabolic, neuroendocrine and behavioural measures. Results show that HFD, but not
PNS, per se led to increased body weight and glucose intolerance. PNS rats fed a
HFD showed resistance to become obese and greater insulin resistance compared to PNS
offspring fed standard chow. As for behavioral measurements, both PNS and HFD lead to
increased anxiety, with greater effects in males. The combination of HFD and PNS protected
from the increased anxiety. Overall these data indicate a programming effect of the prenatal
environment on the metabolic responses of the offspring, in agreement with the “mismatch
hypothesis” and suggest an overlap between metabolic and psychological stressors. Future
studies will assess the mechanisms underlying these effects. This work was supported by
an Era-Net Neuron Grant POSEIDON and Fondazione Cariplo 2012.
(1) Istituto Superiore di Sanità - Italy | (2) University of Milan - Italy
Panetta Pamela | [email protected]
HIGH-FAT DIET DURING PREGNANCY ACTS AS A STRESSOR INCREASING
MATERNAL GLUCOCORTICOIDS' SIGNALING TO THE FETUS AND
DISRUPTING MATERNAL BEHAVIOR THROUGH CHANGES IN NEURONAL
ACTIVITY IN THE OLFACTORY BULB IN C57BL/6J MICE
Bellisario, Veronica (1) | Panetta, Pamela (1) | Balsevich, Georgia (3) | Baumann, Valentin
(3) | Noble, June (2) | Raggi, Carla (1) | Berry, Alessandra (1) | Seckl, Jonathan (2) |
Schmidt, Mathias (3) | Holmes, Megan (2) | Cirulli, Francesca (1)
Feeding a diet rich in fat during pregnancy can impact maternal behavior as well as the
intrauterine environment, playing a critical role in the programming of offspring's physiology.
In a preliminary study we found a strong association between high-fat diet (HFD) during
pregnancy and increased cannibalistic episodes and dams' mortality during late pregnancy and
parturition. Based upon these data, we hypothesized that HFD during pregnancy could
negatively affect neuroendocrine regulations occurring during the final stages of pregnancy,
disrupting maternal behavior. To test such hypothesis, female C57BL/6J mice were fed HFD or
control diet both before and during pregnancy for 11 weeks up to delivery. HypothalamicPituitary-Adrenal (HPA) axis activity and the levels of c-Fos in the olfactory bulbs were
measured both before and after delivery. Dam's emotional behavior and social anxiety, in
addition to locomotor activity, were assessed before parturition. Placental levels of 11-βdehydrogenase- (11-βHSD) type 1 and type 2, regulating fetal exposure to maternal
glucocorticoids, were also assessed. HFD led to aberrant maternal behavior, with dams showing
behavioral disinhibition and decreased locomotor activity, in addition to reduced expression of
c-Fos in the olfactory bulbs, a crucial brain region for social and olfactory behavior hence
essential for maternal behavior. HFD-feeding resulted in increased peripheral levels of maternal
corticosterone, in addition to reduced efficacy of the placental barrier as indicated by the
reduced activity of 11β-HSD2 and 11β-HSD1 gene expression in this organ. Overall, these data
suggest that HFD acts as a stressful challenge during pregnancy, impairing the neuroendocrine
system and the neural activity of brain regions involved in the processing of relevant olfactory
stimuli, with aberrant consequences on mother's physiology and maternal behavior. Funding:
European Commission, Seventh Framework Programme, project acronym: DORIAN, grant
agreement n. 278603
(1) Istituto Superiore di Sanità - Italy | (3) Max Planck Institute of Psychiatry - Germany | (2)
University of Edinburgh - UK
[email protected] | [email protected] | | [email protected] | [email protected]
| [email protected]
Bellisario Veronica | [email protected]
ANTIPSYCHOTIC-LIKE EFFECTS OF THE DOPAMINE D2 RECEPTOR PARTIAL
AGONIST 2-BROMOTERGURIDE IN RATS
Tarland, Emilia (1) | Franke, Robert, T (1) | Pertz, Heinz, H (1) | Fink, Heidrun (1) | Brosda,
Jan (1)
2-Bromoterguride, a dopamine D2 receptor partial agonist, has previously been shown to have
antipsychotic-like activity in rats without inducing adverse side effects. The conditioned
avoidance response (CAR) and the prepulse inhibition (PPI) of the acoustic startle response were
conducted to verify the antipsychotic potential of 2-bromoterguride. In addition, the effect of
2-bromoterguride on prolactin release was investigated to screen for further potentially side
effects.
In male Sprague-Dawley rats aged 10-15 weeks, the effects of 2-bromoterguride (0.1 and 0.3
mg/kg; i.p.) on (1) the avoidance behavior in the CAR-test 30, 90, 270min and 24h post-injection
and on (2) apomorphine- or phencyclidine (PCP)-induced PPI-deficits were investigated. (3) At
various time points after injection of 2-bromoterguride (1, 2, 4, 8h), the plasma prolactin
concentration was determined by ELISA. Established antipsychotics (haloperidol, clozapine,
aripiprazole) were used as positive controls.
Preliminary results show that 0.3mg/kg 2-bromoterguride significantly decreased CAR at 30 and
90min post-injection in a comparable manner to haloperidol and aripiprazole. Furthermore,
0.3mg/kg 2-bromoterguride antagonized apomorphine- but not PCP-induced sensorimotor
gating deficits in the PPI-paradigm. 2-bromoterguride (0.3mg/kg) triggered a reduced prolactin
release compared to the D2 receptor antagonist haloperidol (0.5 mg/kg).
In the present study, the CAR test revealed that 2-bromoterguride, haloperidol and aripiprazole
decreased avoidance levels, which is indicative of antipsychotic activity. Additionally, 2bromoterguride ameliorated PPI-deficits induced by the D2 agonist apomorphine but not those
induced by the non-competitive NMDA antagonist PCP, which is in agreement with the effect
of various atypical antipsychotics on drug-induced PPI-deficits. Besides, the mild
hyperprolactinemia indicates the drugs´ effect on the pituitary, which is not as distinct as the
effect of the full D2 antagonist haloperidol. Due to the in vitro properties and the in vivo
antipsychotic-like effects of 2-bromoterguride, the terguride derivative may be a promising
candidate for the treatment of schizophrenia with a low risk to induce side effects.
(1) Institute of Pharmacology and Toxicology - School of Veterinary Medicine - FU Berlin - Germany
Brosda Jan | [email protected]
DISSOCIABLE EFFECTS OF ANTERIOR THALAMIC LESIONS ON
ATTENTIONAL SET-SHIFTING IN RATS
Nelson, Andrew, J (1) | Wright, Nicholas, F (1) | Vann, Seralynne, D (1) | Aggleton, John, P
(1)
There is very good evidence that the prefrontal cortex, in conjunction with subcortical afferents,
mediates the ability to adapt to changing environmental contingencies. The anterior thalamic
nucleus, a subcortical structure intimately interconnected with the prefrontal cortex, is known
to be important for spatial memory but a role in executive function has received little attention.
The current study examined whether the anterior thalamus is involved in attentional processes
akin to those of prefrontal regions to which it projects. Two separate cohorts of rats with
neurotoxic lesions in the anterior thalamus were tested on an attentional set-shifting paradigm
that measures both the ability to attend to stimuli dimensions that are reliable predictors of
reinforcement (intra-dimensional shift) as well shift attention from one stimulus dimension to
another, previously irrelevant, dimension, when contingencies change (extra-dimensional shift).
In marked contrast to the effects of prefrontal lesions, anterior thalamic damage disrupted
intra-dimensional shifts but facilitated extra-dimensional shifts, as these animals were slower
to acquire discriminations based on the currently relevant stimulus dimension but acquired
discriminations involving previously irrelevant stimulus dimensions more rapidly than control
animals. Further tests indicated that the critical determinant of whether anterior thalamic
damage facilitated the acquisition of an extra-dimensional shift is the degree to which the
stimulus dimension has been established as an unreliable predictor of reinforcement. These
findings suggest that the anterior thalamus is vital for attending to those stimuli that reliably
predict reward. In their absence, attentional control is hijacked by poor predictors of reward.
(1) Cardiff University Wales
[email protected]
Nelson Andrew J D | [email protected]
DYSREGULATION OF ENERGY BALANCE IN CRTC1 MUTANT MICE
Clara Rossetti-Marcon1,2, Daniel Sciarra 1, Olivier
Benjamin Boutrel1,2 and Jean-René Cardinaux1,2
Halfon2,
Pierre J. Magistretti1,3,4,
Obesity is a growing health concern worldwide. This pathological condition is due to an
imbalance between energy intake and energy expenditure. CRTC1 (CREB-regulated
transcription coactivator-1) controls the transcription of many CREB-target genes, some of
which are involved in energy balance. Previous published observations show that Crtc1 is
strongly expressed in the hypothalamus, a key brain structure in energy regulation, and mice
lacking Crtc1 present an obese phenotype.
The aim of this work was to investigate the role of CRTC1 in energy intake and expenditure in
both male and female Crtc1-/- mice. Alterations in energy intake were assessed using three
different approaches: measuring body weight and food consumption, evaluating the expression
of multiple genes in the arcuate nucleus of hypothalamus by qRT-PCR, and determining the
integrity of the rewarding system by testing the preference and the motivation for saccharine.
Finally, the influence of CTRC1 on energy expenditure was assessed through the measure of
locomotor activity.
Our results show the presence of a sexual dimorphism in the obese phenotype of Crtc1-/- mice:
males gain more weight than females and are hyperphagic. Moreover, only in males, obesity is
accompanied by changes in the expression of energy balance-related genes. No difference in
saccharine preference has been found in mutant mice, whereas the lack of Crtc1, in both sexes,
reduces saccharine taking behavior in an operant paradigm. Finally, compared to controls a
perturbed pattern of locomotor activity has been observed in all mutant mice. Collectively,
these findings clearly confirm a role of CRTC1 in the regulation of energy balance and suggest
that females are less affected by the lack of this transcriptional coactivator.
1Center
for Psychiatric Neuroscience – 2Service of Child and Adolescent Psychiatry, Department
of Psychiatry, Lausanne University Hospital, Switzerland. 3KAUST, Thuwal, Saudi
Arabia. 4Brain Mind Institute, EPFL, Lausanne, Switzerland
Rossetti-Marcon, Clara | [email protected]
VALUE OR VALENCE? DIFFERENCES IN THE NEURAL SIGNATURE OF
REWARD AND PUNISHMENT IN VISUAL ENCODING
Barbaro, Ludwig, P. (1) | Peelen, Marius, V. (1) | Hickey, Clayton (1)
During visual search in natural scenes attention to a category of visual stimuli can be indexed
in multi-voxel patterns of fMRI activity in occipito-temporal cortex. When various relevant
objects are presented concurrently, there is a relative enhancement of the representation of
the category of the attended object and an active suppression of the category information of
objects acting as distractors. Pairing of a category with reward boosts these effects:
information for reward-associated targets increases and there is stronger suppression of
information about reward-associated distractors. Here we extend these existing results to
examine the encoding of a punishment-associated category. Our task was such that correct
detection of reward- and punishment-associated targets had the same relative value (100
points), but detection of a reward-associated target resulted in the receipt of 150 points (vs.
50 points for incorrect performance) whereas detection of a punishment-associated target
resulted in the loss of 50 points (vs. the loss of 150 points for incorrect performance). Our aim
was to tease apart the influence of valence and value on visual representation. Results
demonstrate that while rewarded categories show an increased level of information when
acting as targets and a decreased level when acting as distractors with respect to the neutral
category, there is no such relative decrease of information for the punished category when
acting as distractor. This is consistent with an associated behavioral experiment in which
reward-associated objects disrupt search to a greater degree than punishment-associated
objects. We conclude that the effect of motivational feedback on categorical representation in
object-selective perceptual areas not only depends on the value but also on the valence of the
feedback.
(1) Univ Trento - Italy
Barbaro Ludwig P | [email protected]
PERFORMANCE ON A NOVEL TOUCHSCREEN RODENT CONTINUOUS
PERFORMANCE TEST IS SENSITIVE TO MEDIAL PREFRONTAL CORTEX
LESIONS IN MICE
Hvoslef-Eide, Martha (1) | Mar, Adam, C (2) | Hailwood, Jonathan, M (1) | Robbins, Trevor,
W (1) | Saksida, Lisa, M (1) | Bussey, Timothy, J (1)
Behavioural tasks that translate easily across species are highly valuable both when evaluating
potential new treatment compounds, as well as in the context of understanding the
neuroanatomical and neurophysiological contributions to cognitive function across species. The
Continuous Performance Task (CPT; Rosvold et al, 1956) is a test of visual selective and
sustained attention that has been widely used in clinical research, and has proven sensitive for
detecting deficits across a number of conditions associated with dysfunction of the prefrontal
cortex, including early impairments in both patients with schizophrenia (Asarnow & MaCrimmon,
1978) and non-affected relatives (Rutschmann et al, 1977). The newly developed touchscreen
rodent CPT (rCPT) has been designed to be highly analogous to the human CPT and provides
near-identical measures of selective and sustained visual attention. The current study describes
the effects of medial prefrontal cortex lesions in mice on rodent CPT performance. Following
recovery from bilateral quinolinic acid (2,3-Pyridinedicarboxylic acid) induced medial
prefrontal cortex infusions or sham lesions with vehicle infusions, rCPT performance as defined
by d' (sensitivity measure) was lower in lesioned mice compared to shams, particularly when
stimulus durations were short, or inter-trial interval was lengthened. The performance deficit
was driven largely by an increase in false alarm rate (higher responding to non-target stimuli)
compared to sham mice. There were no significant differences in hit rate (responding to target
stimuli). The study demonstrates that the touchscreen CPT task can be successfully
implemented in mice, with task performance being sensitive to the functional integrity of the
medial prefrontal cortex.
(1) University of Cambridge - United Kingdom | (2) New York University Medical Center - U.S.A.
Email: [email protected] |
Hvoslef-Eide Martha | [email protected]
REDUCTION OF ADULT HIPPOCAMPAL NEUROGENESIS MODIFIES BRAIN
FUNCTIONAL CONNECTIVITY AND ENHANCES COCAINE-SEEKING IN MICE
Castilla-Ortega, Estela (1) | Ladrón de Guevara-Miranda, David (1) | Blanco, Eduardo (2) |
Serrano, Antonia (1) | Pedraz, María (1) | Estivill-Torrús, Guillermo (1) | Pavón, Francisco, J
(1) | Rodriguez de Fonseca, Fernando (1) | Santín, Luis, J (2)
Adult hippocampal neurogenesis has been proposed as a putative neuroplastic mechanism
involved in the contextual memories related to drug addiction. In this work, we studied the
effect of the inhibition of adult hippocampal neurogenesis using the DNA alkylating agent
temozolomide (TMZ), in cocaine-induced conditioned place preference (CPP) behaviour. In a
first experiment, we investigated both CPP acquisition/expression and the functional brain
circuits underlying CPP expression in control and neurogenesis-reduced conditions by analysing
c-Fos immunoreactivity (c-Fos IR) in hippocampal and extrahippocampal addiction-related
areas. A second experiment was designed to study the involvement of adult-born neurons in
the extinction and cocaine-induced reinstatement of drug-seeking in the CPP model. We
performed two independent studies where adult hippocampal neurogenesis was inhibited either
before or after the CPP was acquired. Our results showed that TMZ treatment had no effect on
the acquisition of the cocaine-induced CPP, but c-Fos IR associated to the test trial (CPP
expression) revealed an increased activity in some of the analysed brain areas in the CPP-TMZ
mice. Correlational and multivariate analysis revealed that, under normal conditions, the
hippocampus showed widespread functional connectivity with other brain areas and strongly
contributed to the functional brain network associated with CPP expression. However, mice
with reduced neurogenesis showed an alternative brain circuit. The results of the second
experiment revealed that mice acquiring the cocaine-induced CPP under neurogenesis-reduced
conditions were delayed in extinguishing their drug seeking behaviour. However, when
neurogenesis was inhibited after CPP acquisition, extinction was not affected but an enhanced
long-term CPP retention was found, suggesting that the role of the adult-born neurons may
differ depending on whether they are generated before or after drug-contextual associations
are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased
in the TMZ mice, regardless of the time of neurogenesis inhibition. Funding: PSI2013-44901-P
and SEJ-4515.
(1) Instituto de Investigación Biomédica de Málaga (IBIMA) - Hospital Regional Universitario de Málaga
- Spain | (2) Universitat de Lleida - Spain
Ladrón de Guevara-Miranda David | [email protected]
MEMORY UNDER STRESS: TESTING THE ROLE OF THE DORSOLATERAL
PREFRONTAL CORTEX THROUGH NONINVASIVE BRAIN STIMULATION
Bogdanov, Mario (1) | Schwabe, Lars (1)
Stress is ubiquitous in modern societies and may contribute to mental disorders such as
depression or posttraumatic stress disorder. These effects of stress are at least partly due to
stress hormones acting on limbic or prefrontal structures, thus changing cognitive processes.
For instance, stress is known to impair cognitive functions depending on the dorsolateral
prefrontal cortex (dlPFC), such as working memory or the retrieval of episodic memories. Here,
we tested whether stress-induced changes in working memory and memory retrieval can be
prevented by non-invasive stimulation of the dlPFC through transcranial direct current
stimulation (tDCS). To this end, we exposed 120 participants to a stress or control protocol
before they performed working memory tasks and a retention test for previously learned
material. Critically, during the working memory and retrieval tasks, participants received either
anodal, cathodal or sham stimulation of the right dlPFC. We hypothesized that stress would
induce impairments in all memory tasks and that anodal, but not cathodal or sham, stimulation
of the right dlPFC would ameliorate these effects. Data are currently analyzed and will be
presented at the conference.
(1) Department of Cognitive Psychology - Institute for Psychology - University of Hamburg - Germany
Bogdanov Mario | [email protected]
EFFECTS OF SECOND-GENERATION ANTIPSYCHOTICS ON NEUROGENESIS
AND NEURODEGENERATION IN DENTATE GYRUS OF THE HIPPOCAMPUS
Köktürk, Sibel (1) | Mutlu, Oguz (2) | Ulak, Guner | Akar, Furuzan | Erden, Faruk |
Celikyurt, Ipek | Bektas, Emine | Tanyeri, Pelin
The antipsychotic drugs, perospirone, ziprasidone, aripiprazole and paliperidone are widely
prescribed to treat schizophrenia and other psychotic disorders. The role of second-generation
antipsychotics in schizophrenia is not fully understood. There are a significant number of side
effects associated with antipsychotic drugs. Neurogenesis induced by brain ischemia implies
that damaged neuronal function may be repaired by replacing lost neurons with
bromodeoxyuridine (BrdU) labelled neurons in the subgranular zone (SGZ) of the hippocampal
dentate gyrus (DG).
The aim of this study was to determine the effects of these drugs on neurogenesis and
neurodegeneration in DG of the hippocampus in the brain of naive mice, using BrdU
immunohistochemistry and Hematoxylin-eosin (H&E) stainings. Mice were intraperitoneally
treated chronically with perospirone (0,50 mg/kg), ziprasidone (1 mg/kg), aripiprazole (6
mg/kg) and paliperidone (0,50 mg/kg) for 15 days. Mice were intraperitoneally injected with
BrdU (50 mg/kg) and were killed 24 hours later. Hippocampal sections were collected and
processed for BrdU immunohistochemistry and H&E stainings. BrdU labeled cells in the DG were
then counted, and compared to determine the degree of neurogenesis.
Our results showed that perospirone and ziprasidone significantly increased the number of BrdU
labeled cells while aripiprazole and paliperidone decreased in the DG. However, neuronal
damage was higher in the perospirone and ziprasidone groups than in aripiprazole and
paliperidone.
In psychotic disorders should be considered neuroprotective and suppressive or proliferative
effects on neurogenesis besides effectiveness of the antipsychotic drugs. Further studies are
needed to clarify the neurogenesis and neurodegeneration in the antipsychotic treatments.
(1) Department of Histology and Embriyology - Medical Faculty - Ordu University - Ordu - Turkey | (2)
Department of Medical Pharmacology - Psychopharmacology Lab. - Medical Faculty - Kocaeli University
- Kocaeli - Turkey
Oguz Mutlu | [email protected]
IMPACT OF ADVERSE PEER-EXPERIENCES IN ADOLESCENT RATS ON
ETHANOL INTAKE AND ENDOCANNABINOID SIGNALING IN LATER LIFE
Schneider, Miriam (1) | Friemel, Chris (2) | Schneider, Peggy (2) | Bindila, Laura (3) | Lutz,
Beat (3)
Peer-interactions become particularly important during adolescence and hence, human
teenagers display enhanced sensitivity towards social rejection. Neurobiological consequences
of social rejection during adolescence have not yet been well investigated and no appropriate
animal model is available. Here, we studied the potential adverse consequences of inadequate
social encounters in adolescent rats, which we propose as an operational model for adolescent
peer-rejection. Male adolescent Wistar rats were either reared with other Wistar animals
(control), or with age-matched rats from the Fischer344 strain which have been shown to differ
in social play behavior from Wistar rats (inadequate social rearing; play-deprived). From day 65
on, all Wistar rats were again group-housed with same strain partners. Voluntary ethanol intake
was assessed in Wistar animals throughout adolescence and in adulthood. In addition, levels of
the endocannabinoids anadamide (AEA) and 2-arachidonylglycerol (2-AG), as well as protein
levels of the CB1 receptor were measured in adult Wistar animals. Animals reared with
inadequate social partners showed increased ethanol intake during adolescence as compared
to controls, which persisted into adulthood. The two groups exhibited differences in the
expression levels of the CB1 receptor and concentration of endocannabinoids, which were most
pronounced in the amygdala. In conclusion, adverse social experiences during adolescence
result in distinct acute and persistent behavioral and neurobiological alterations which promote
ethanol intake.
(1) Research Group Developmental Neuropsychopharmacology - CIMH Mannheim - Germany | (2) CIMH
| (3) Institute Physiological Chemistry - University Mainz - Germany
Schneider Miriam | [email protected]
MATERNAL SEPARATION INDUCES BEHAVIOURAL ALTERATIONS AND
NEUROINFLAMMATORY REACTIONS IN A SEX-DEPENDENT WAY IN MICE
Gracia-Rubio, I (1) | Moscoso-Castro, M (1) | Pozo, O, J (2) | Marcos, J (2) | Nadal, R (3) |
Valverde, O (1)
Early life experiences play a key role in brain function and behaviour. Adverse events during
childhood are therefore a risk factor for psychiatric disease during adulthood, such as mood
disorders. Maternal separation is a validated mouse model for maternal neglect, producing
negative early life experiences that result in subsequent emotional alteration. Depressive
disorders have been found to be associated with neurochemical changes and neurotransmitter
deficits such as reduced availability of monoamines in discrete brain areas. Depressive states
result in reduced serotonin availability and enhanced kynurenine metabolism through the action
of indoleamine 2, 3-dioxygenase in response to neuroinflammatory factors. This mechanism
involves regulation of the neurotransmitter system by neuroinflammatory agents, linking mood
regulation to neuroinmunological reactions. In this context, the aim of this study was to
investigate the effects of maternal separation with early weaning on emotional behaviour in
mice. We also investigated neuroinflammatory responses and the state of the tryptophankynurenine metabolic pathway in discrete brain areas following maternal separation. We show
that adverse events during early life increase risk of long-lasting emotional alterations during
adolescence and adulthood. These alterations are particularly severe in females. Behavioural
alterations were associated with microglia activation and disturbed tryptophan-kynurenine
metabolism in brain areas related to emotional control. This finding supports the preeminent
role of neuroinflammation in emotional disorders.
This study was supported by MINECO (SAF2013-41761-R-FEDER), Ministry of Health (Retic-ISCIIIRD/12/0028/0014-FEDER and Retic-ISCIII-RD/12/0028/0024-FEDER), Plan Nacional sobre Drogas
(2014/020), and Generalitat de Catalunya (2014SGR34 . IG-R was funded by FPI fellowship BES2011-046655.
(1) Universitat Pompeu Fabra-Spain | (2) IMIM-Spain | (3) Universitat Autònoma de Barcelona-Spain
Gracia-Rubio I | [email protected]
BEHAVIOURAL AND NEUROINFLAMMATORY CHANGES INDUCED BY THE
GENETIC BLOCKADE OF ADENOSINE A2A RECEPTORS: RELEVANCE TO
SCHIZOPHRENIA
Moscoso, Maria (1) | Gracia, Irene (1) | Ciruela, Francisco (2) | Valverde, Olga (1)
Schizophrenia is a chronic, severe and debilitating mental disorder with a presumed
neurodevelopmental origin affecting about 0.5 to 1.0 percent of the population worldwide. The
clinical features of the disease include I) positive symptoms; II) negative symptoms; III)
cognitive deficits; and IV) minor motor deficits. Despite being one of the most costly brain
disorders to our society, the etiology remains elusive and so far no effective treatments to
prevent or relieve all the symptoms of the disease have been developed. The pathophysiology
of schizophrenia has classically studied the involvement of dopamine and glutamate. However,
new hypothesis have arisen adding adenosine as a putative affected neurotransmitter
system.A2A receptors, in which we have focused our work, are highly expressed in areas
controlling motivational responses and cognition including striatum, hippocampus, cerebral
cortex and glia. In this context, the aim of our study was to useA2A receptor knockout (KO)
mice with complete and specific inactivation of the A2A receptor as an
endophenotype model of schizophrenia. To achieve this goal, we performed different
behavioural paradigms to assess schizophrenic-like symptoms in adult male KO and wild-type
(WT) littermates. Our results showed an overall impairment in response inhibition and sensory
gating in KO animals that was assessed by prepulse inhibition and latent inhibition tests. The
hyperlocomotion induced by d-amphetamine and MK-801 was found to be reduced in KO animals
when compared to WT littermates. Moreover,A2A animals showed motor disturbances and
depressive like-responses, evaluated with the rotarod and tail suspension test respectively.
Cognitive evaluation showed severe cognitive deficits, as seen in the radial arm maze and
object recognition test. Finally, behavioural alterations were associated with microglia
disruptions in hippocampus ofA2A animals. Altogether; our data support the role of adenosine
in schizophrenia and postulateA2A KO animals as a new mouse model of the disorder.
(1) Universitat Pompeu Fabra - Spain | (2) Universitat de Barcelona - Spain
Moscoso Maria | [email protected]
“TWO-HIT” DEVELOPMENTAL MODEL OF SCHIZOPHRENIA: RESCUE OF
JUVENILE CHANGES BY PREGNENOLONE
Schifani, Christin (1) | Rêlo, Ana-Lucia (1) | Klein, Corinna (1) | Bespalov, Anton (1)
Maternal infection and/or stress during brain development of the offspring are thought to lead
to increased cytokine levels and neuroinflammation which can cause lasting changes in the
developing brain. Studies using neurodevelopmental animal models including maternal immune
activation (MIA), postnatal stress or early glutamatergic insult lead to changes in microglia or
GABAergic neurotransmission, comparable to what can be find in schizophrenia patients. It is
hypothesized that early treatment intervention could be used to treat changes seen already
during adolescence, however, useful treatment is still lacking. Therefore, our study focusses
first on assessing neuroinflammation via changes in microglia during late adolescence (PND 48)
in a two-hit developmental animal model. The model mimics the two-hit hypothesis by
combining two environmental factors known to be at risk for schizophrenia, MIA during
pregnancy (via polyinosinic-polycytidylic acid (Poly I:C) infusion on gestation day 15) and early
life insult (via neonatal exposure of offspring to glutamatergic insult by repeated treatment
with an NMDA receptor antagonist phencyclidine (PCP) on postnatal days 7, 9 and 11).
Furthermore, the resulting changes in GABAergic transmitter system were monitored. Rats
treated with both hits showed an increased number of microglia (quantified by Iba-1 staining)
in the hippocampus. Additionally, those rats had an increased GAD67 immunostaining not only
in the hippocampus but also in the prefrontal cortex. Second, to prevent the neuroinflammation
by the two-hit treatment, we decided to treat the rats with pregnenolone, a neurosteroid
shown to have neuroprotective potential, for 14 days during adolescence. Number of microglia
as well as changes in GABAergic neurotransmission were back to control levels. To conclude,
two hit treatment, combining MIA and early glutamatergic insult, can be used as a model to
assess early neuroanatomical changes in microglia and GABAergic signaling. Additionally,
pregnenolone seems to have protective effects and may be applicable for preventive treatment
during the early phase of schizophrenia or other neurodevelopmental disease.
(1) AbbVie - Germany
[email protected]
Schifani Christin | [email protected]
ROLE OF THE ENDOCANNABINOID SYSTEM IN THE BEHAVIORAL
ABNORMALITIES OBSERVED IN THE RAT VALPROIC ACID MODEL OF
AUTISM.
Melancia, Francesca (1) | Servadio, Michela | De Fulvio, Federica (1) | Picerno, Fabiana (1) |
Cartocci, Veronica (1) | Pallottini, Valentina (1) | Trezza, Viviana (1)
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, altered
communication and repetitive behaviors, often accompanied by “associated symptoms” (e.g.,
anxiety, cognitive deficits). Prenatal exposure to valproic acid (VPA) has been proposed as a
preclinical model of ASD. The first purpose of this study was to investigate whether VPA
prenatal exposure induces ASD-like symptoms in the adolescent and adult rat offspring. The
second purpose of this study was to analyze possible biochemical alterations of the
endocannabinoid system in different brain regions of VPA-exposed rats and to test if
pharmacological manipulations of the endocannabinoid system revert the behavioral alterations
displayed by VPA-exposed animals. Female Wistar pregnant rats were treated with VPA or saline
solution at gestational day 12. The adolescent and adult male offspring was tested in the social
interaction and elevated plus maze (EPM) tests. In the social interaction test, the social
behaviors, both related and unrelated to play, and the 50-kHz ultrasonic vocalizations (USVs)
emitted during the social encounter were analyzed. The adolescent and adult offspring was
also tested in the EPM test, the most common animal model of anxiety. Both in adolescence
and adulthood, VPA-exposed animals showed altered patterns of social behavior and USV
emission during the social encounter, and an anxious-like phenotype in the EPM test compared
to saline-exposed rats. Biochemical analysis revealed a different phosphorylation level of CB1
cannabinoid receptors between two experimental groups in amygdala, hippocampus and dorsal
striatum. Treatment with the anandamide hydrolysis inhibitor URB597 corrected the altered
behaviors displayed by VPA-exposed animals in the EPM test; ongoing experiments are
evaluating its effects on the altered social behavior displayed by VPA-exposed rats. These
findings reveal that embryonic exposure to VPA in rats provides a good model of ASD and is a
valuable tool to explore new pharmacological targets for these diseases.
(1) Roma Tre University Italy
| [email protected] | [email protected] | [email protected] |
[email protected]
Melancia Francesca | [email protected]
ROLE OF ADULT HIPPOCAMPAL NEUROGENESIS IN SPATIAL MEMORY
RECONSOLIDATION
Lods, Marie (1) | Ferreira, Guillaume (2) | Pacary, Emilie (1) | Goron, Adeline (1) | Abrous,
Nora, Djoher (1) | Tronel, Sophie (1)
Following learning, memory is labile and stabilizes over time through a process of
consolidation. However a stable memory can become labile again if reactivated and thus a
reconsolidation process is needed to re-stabilize memory. Whereas a great amount of studies
have investigated cellular and synaptic mechanisms of reconsolidation in particular in the
hippocampus, reconsolidation has not yet been considered in the context of ongoing adult
hippocampal neurogenesis, a process known to confer a new support to memory formation.
We have recently demonstrated that spatial learning in the water maze selects a population of
immature neurons, increases its survival and dendritic arborisation. However, these neurons do
not participate to this particular spatial learning since too immature. Indeed, adult-born
neurons participate to memory processes when they are functionally integrated into the
hippocampal network. Thus, the specific role of this selected population remains to be defined.
Our hypothesis is that this population when reaching functional maturity is involved in spatial
memory reconsolidation.
To address this question, BrdU was injected in rats one week before water maze training. Four
weeks later animals were submitted to a reactivation session and they received icv infusions of
anisomycin, a protein synthesis inhibitor or alternatively a vehicle solution. They were tested
two days later and were killed ninety minutes after that, in order to analyze cell activation.
Our results show that anisomycin treated rats encounter impaired retention compared to
vehicle treated-animals. Using a functional imaging approach, we analysed the activation of
BrdU positive cells. We demonstrated that this selected population is specifically activated by
memory reconsolidation. Then, we developed a new pharmacogenetic approach to tag and
manipulate a specific adult-born neuron population in rat.
Preliminary data suggests that there is a causal relationship between this population of adultborn neurons selected by learning and spatial memory reconsolidation.
(1) Neurocentre Magendie Inserm U862-Bordeaux-France | (2) NutriNeuro-Bordeaux-France
Tronel sophie | [email protected]
EFFECTS OF EARLY OR LATE WEANING ON MOUSE BEHAVIOR
Gioiosa, Laura (1) | Superchi, Cecilia (1) | Pizzi, Francesco (1) | Parmigiani, Stefano (1) |
Palanza, Paola (1)
Early life events affect behavioral development and vulnerability to stress later in life.
Particularly crucial is the role of mother-offspring interactions. Weaning is a step-by-step
process of maternal separation occurring during several days with behavioral and physiological
consequences on the offspring.
Aim of our study was to validate an animal model of early stress and analyze the effects of age
at weaning on behavioral development and stress response of offspring later in life in CD1 mice.
To evaluate the effect of weaning on behavior and metabolism in mice, we weaned mice at
different ages. Therefore, our experimental design consisted of early-weaned mice (postnatal
day -PND 19), late-weaned mice (PND 30) and standard-weaned mice (PND 25). We measured
body weight growth weekly and as adults mice underwent the Elevated Plus Maze (EPM), social
open field and resident/intruder tests.
Adult early-weaned females were significantly heavier than late-weaned females, as opposed
to males, which did not differ on the basis of weaning age. As adults, half of the experimental
animals underwent 30-min restrained stress and the remaining were left undisturbed in their
home-cages (controls). Afterwards, all mice were observed on the EPM test. Among controls,
early-weaned mice were significantly less anxious-like compared to standard-weaned mice.
After restrained stress, early-weaned mice significantly decreased the time spent in open arms
so that they resulted significantly more anxious-like than early-weaned controls. In the
remaining behavioral tests, we did not observed significant differences between early- and
late-weaned mice.
In conclusion, we observed a greater body weight growth in early-weaned females compared
to controls and less anxiety-like in early-weaned mice, as opposed to the increased anxiety in
restrained, early-weaned mice. Present results should be taken in to account when designing
experiments and during experimental and breeding procedures.
Funding source -PRIN 2008 and University of Parma
(1) University of Parma - Italy
Gioiosa Laura | [email protected]
DIFFERENT LEARNING CAPABILITIES OF RAT STRAINS IN TWO
ATTENTIONAL TEST PARADIGMS
Kassai, Ferenc (1) | Plangár, Imola (1) | Kozma, Kata (1) | Ernyei, Aliz, J. (1) | Gyertyán,
István (1)
The 5-choice serial reaction time task (5CSRTT) measures the sustainability of attention, while
the attentional set shifting test (ASST) assesses the flexibility in changing its focus. We
compared the learning capabilities of Long Evans (LE), Charles River (ChW) and Hannover Wistar
rats (HW) in these paradigms.
Animals were trained in two different paradigms in the 5CSRTT. In the usual “light on” version,
rats had to nose-poke into that hole where the light was turned on. In the “light off” paradigm,
assumed to be more difficult, all holes were lit and the stimulus animals were required to
respond to was turning off the light in one of the holes. ASST training was performed in a newly
developed test box, where the stimulus cues (odor and floor texture) signaled the entrance to
the reward-containing chamber. In this setup choices are more unequivocal, and animals cannot
find the reward by its smell. Animals were also tested on the elevated plus-maze to assess their
anxiety level- a factor which may influence learning performance.
ChW learnt both the “light on” and the “light off” 5CSRTT paradigms significantly slower than
LE and HW. Whereas the latter two strains did not differ in their performance in the “light on”
version, LE was remarkably superior to HW in the “light off” task. In contrast, ChW advanced
quicker in acquiring the sequential steps of the ASST than either HW or LE. On the plus-maze,
ChW spent significantly more time in the open arms than the other two strains.
The observed strain differences may result from the different capabilities in handling distinct
aspects of attention. The low anxiety behavior of ChW may also contribute to their good ASST
learning, because in this test animals continuously interact with the experimenter, which is
supposedly a stressful situation for them.
(1) MTA-SE NAP B Behavioural pharmacology group - Hungary
Kassai Ferenc | [email protected]
GROUP II MGLU RECEPTOR ANTAGONIST, LY341495 ENHANCES
ANTIDEPRESSANT-LIKE EFFECTS OF KETAMINE IN THE FORCED SWIM TEST
IN RATS
Pałucha-Poniewiera, Agnieszka (1) | Podkowa, Karolina (1) | Rzeźniczek, Szymon (1) | Pilc,
Andrzej (1)
The slow onset of action is one of the most important disadvantages of antidepressant drugs
currently used in the clinic. On the other hand, both preclinical and clinical studies have
reported the rapid and sustained antidepressant effects of the NMDA receptor antagonist,
ketamine. Since ketamine induces several undesirable effects which make it a dangerous drug,
a variety of strategies have been suggested to avoid such effects. Here we propose to enhance
the sub-effective doses of ketamine by the co-administration with the group II mGlu receptor
antagonist, LY341495, which has been suggested as a potential antidepressant acting via
mechanism similar to ketamine. The forced swim test (FST) in rats has been chosen to the study,
and the tested compounds (ketamine and LY341495) have been used individually or in the
combinations, both 40 min and 24 h before the FST, in order to investigate the rapid and
sustained antidepressant-like effects of these drugs. We have found that sub-effective doses of
ketamine and LY341495, given jointly, induce significant antidepressant-like effects, both 40
min and 24 h after administration. The effect of test substances on the spontaneous locomotor
activity of rats in the ranges of times and doses of both substances was excluded. Furthermore,
the results obtained from the rota-rod test and the ketamine-induced hyperlocomotion test
suggest a lack of potential adverse effects of the combination of ketamine and LY341495 at
doses previously used in the FST. Altogether, these data suggest that the joint administration
of ketamine and LY341495 might be a noteworthy alternative to the use of solely ketamine in
the therapy of depression.
Acknowledgements:
This work was supported by grant No. 2014/13/B/NZ7/02222 to A.P-P. assigned by the National
Science Centre, Poland and by Funds for Statutory Activity of the Institute of Pharmacology
Polish Academy of Sciences in Kraków.
(1) Institute of Pharmacology Polish Academy of Sciences - Poland
Pałucha-Poniewiera Agnieszka | [email protected]
INCREASED SEROTONIN CONCENTRATION IN THE RAT BRAIN EVOKED
SYMPTOMS OBSERVED IN PEOPLE WITH AUTISM SPECTRUM DISORDERS
Ptaszek, Kacper (1) | Plucinska, Karolina (1) | Jurkowlaniec, Edyta (1)
Almost one-third of people with Autism Spectrum Disorders (ASD) have elevated platelet
serotonin (5-HT) level. Different authors suggest that dysfunctions of the serotonergic system
may be connected with gastrointestinal problems, depression and anxiety. These symptoms are
very often observed in people with ASD, probably as a result of the blood-brain barrier
permeability in children under 2 years old, when elevated peripheral 5-HT may be transferred
from blood into the brain and cause impairments of the serotonergic system.
To understand the influence of the elevated 5-HT level in the brain we analysed whether the
5-HT injection into the lateral ventricle in rats evoke behaviours present in people with ASD.
Male Wistar (N=10) rats had cannulas implanted into the lateral ventricle under isoflurane
anaesthesia with butorphanol analgesia. After two weeks of convalescence animals were
divided into groups receiving 5-HT (dissolved in 0.9% NaCl) infusion at a dose of 5 mg/kg b.w.
and volume of 0.5 µl or NaCl infusion. Before the infusion period, either locomotor activity or
body weight had been measured by a week. Anxiety level (4th day) and social activity (8th day)
measurements were also planned during the 11-day infusion period.
The locomotor response to novelty between groups was comparable (2300 movements in
horizontal plane in 30 minutes), and so was the basal locomotor activity before infusion, but
after 5-HT infusion rats were significantly less active (Students’ t: 0.05). Surprisingly, the 5-HT
infusion caused significant loss of weight the next day after the first dose (Students’ t: 0.01).
The anxiety level, measured as the time spent in the closed arms in the elevated plus maze,
was increased in rats receiving 5-HT (Students’ t: 0.05).
The obtained results suggests that increased 5-HT level in the brain evokes symptoms
characteristic of ASD.
The research was funded by Young Researcher 2014 grant, 538-L124-B598-14.
(1) Department of Animal and Human Physiology - University of Gdansk - Gdansk - Poland
[email protected]
Ptaszek Kacper | [email protected]
THE ROLE OF GABAB RECEPTOR IN THE ANTIPSYCHOTIC-LIKE ACTION OF
MGLU4 RECEPTOR ORTHOSTERIC AGONIST LSP4-2022
Wieronska, Joanna, M (1) | Wozniak, Monika (1) | Acher, Francine (2) | Pilc, Andrzej (1)
Variety of the previous research showed that the action of the ligands of metabotropic
receptors for glutamate is dependent on the others neurotransmitters in the central nervous
system. Here, we assessed the involvement of GABAB receptors in the action of LSP4-2022 in
several behavioral models for positive, negative and cognitive symptoms of schizophrenia. As
the model for positive symptoms we used MK-801-induced DOI-induced head twitches test in
mice. As the models of negative symptoms we used social interaction test in rats, while
cognitive dysfunction was investigated in the novel object recognition test. As the GABAB
receptor ligand GS39783 (positive allosteric modulator) was used. Our results show that the
action of LSP4-2022 in DOI-induced head twitches test was GABAB-dependent, while those
interaction was not observed in the social interaction and novel object recognition models. Our
results show that LSP4-2022 action involves GABAB signaling but only in positive, but not
negative or cognitive symptoms of schizophrenia.
(1) Institute of Pharmacology Polish Acdemy of Sciences Krakow Poland | (2) Université Paris Descartes
Paris France
Wieronska Joanna | [email protected]
EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS ON INHIBITORY AVOIDANCE
IN MICE AND ITS COMBINATION WITH CLOMIPRAMINE
Monleón, Santiago (1) | Duque, Aránzazu (1) | Vinader-Caerols, Concepción (1)
In this study, the effects of Chronic Social Defeat Stress (CSDS) on Inhibitory Avoidance (IA) in
post-pubertal male CD1 mice and the potential reversing effects of clomipramine were
evaluated. Subjects were randomly divided into four groups (n = 12-14): non-stressed + saline
(NS+SAL); non-stressed + clomipramine (NS+CLO); stressed + saline (S+SAL); and stressed +
clomipramine (S+CLO). Stressed animals were exposed to a daily 10-min social defeat by a
larger and aggressive mouse in its home cage on 20 consecutive days. Each confrontation was
followed by treatment with saline or clomipramine (1 mg/kg, i.p.). 24 h after the last session
of CSDS, mice were evaluated in a one-trial step-through version of IA. As complementary tests,
animals were also evaluated in the elevated plus maze for 5 min (locomotor activity and
emotionality measures) as well as in the hot plate paradigm (analgesia measure). IA learning
(test latencies significantly higher than training latencies) was confirmed in the non-stressed
groups (NS+SAL and NS+CLO) but not in the stressed groups (S+SAL and S+CLO). No significant
differences were observed in either motor activity or analgesia. In conclusion, this degree of
CSDS prevents the memory formation of IA in mice, whilst the dose of clomipramine tested is
ineffective in reversing this impairment. Furthermore, these effects of CSDS on memory are
not secondary to motor, emotional or analgesia effects of stress.
(1) University of Valencia - Spain
Monleón Santiago | [email protected]
RAPID AND REFINED SCREENING OF BEHAVIORAL FLEXIBILITY,
IMPULSIVITY AND ATTENTION IN MICE USING DIFFERENT TYPES OF
AUTOMATED HOME-CAGE TASKS
Remmelink, Esther (1,2,3) | Verhage, Matthijs (2) | Smit, August, B. (3) | Loos, Maarten (1)
Several brain disorders, such as schizophrenia and autism, are characterized by deficits in
cognitive flexibility, attention and inhibitory control. The majority of currently available
behavioral tests to assess these functions in animal models of brain disorders are labor intensive,
require imposed food-restriction regimes and involve extended training periods. Therefore, we
investigated whether in a home-cage setting, with 24-hour access to an operant task and
without imposed food-restriction regimes, mice would reach similar performance levels in a
shorter training period. We describe 3 new operant protocols for automated home-cages that
measure behavioral flexibility, sustained attention, impulsivity, and attentional set-shifting.
1. First, we developed a reversal learning task that effectively measures initial discrimination
learning and behavioral flexibility within 4 days in an automated home-cage. In line with
previous studies, MK801 injections disrupted initial discrimination learning, while lesioning the
orbitofrontal cortex led to a specific reversal learning deficit.
2. We adapted a five choice serial reaction time task (5CSRTT) for mice towards a home-cage
setup. Typically, 10 - 14 weeks of daily training sessions are required to measure performance
in a conventional setup. Automation significantly reduced total training time to 2 weeks with
levels of accuracy, omissions, and premature responses comparable to those obtained in the
conventional setup.
3. We designed a novel attentional set-shifting protocol for an operant home-cage setup, in
which mice successfully completed 2 reversals and 1 dimensional shift within 2 weeks.
We observed impairments in mouse lines with well-known deficits in executive function (e.g.
APP/PS1, Fmr1 and some BXD strains) in these automated tasks, replicating as well as extending
previous results. In all tasks, activity was predominantly limited to the dark phase, suggesting
that 24-hour access to the task had no impact on circadian rhythm.
In conclusion, we show that various tasks measuring executive functions can be implemented
effectively in automated home-cage setups without imposed food-restriction regimes.
(1) Sylics (Synaptologics B.V.) - The Netherlands | (2) Department of Functional Genomics - CNCR - VU
University Amsterdam - The Netherlands | (3) Department of Molecular and Cellular Neurobiology CNCR - VU University Amsterdam - The Netherlands
Remmelink Esther | [email protected]
METABOLIC AND IMMEDIATE-EARLY GENE CHANGES IN THE
RETROSPLENIAL CORTEX FOLLOWING MAMMILLOTHALAMIC TRACT
LESIONS.
Milczarek, Michal, M (1) | Frizzati, Aura (1) | Nelson, Andrew, JD (1) | Sengpiel, Frank (1) |
Vann, Seralynne, D (1)
The retrosplenial cortex (RSC) has emerged as an important node within the Papez memory
system, contributing to both spatial and non-spatial cognition. Furthermore, it is particularly
sensitive to damage to other parts of the extended memory network in both patients and
rodents. The RSC is one of the first regions to show hypoactivity in Alzheimer’s Disease; in rats,
lesions of the anterior thalamic nucleus and hippocampus both result in RSC dysfunction,
reflected by downregulation of the immediate-early genes zif268 and c-fos. In
addition, anterior thalamic lesions have been shown to decrease staining for a cellular activity
marker, cytochrome oxidase. As both the anterior thalamic nuclei and the hippocampus directly
innervate the RSC, it is possible that these changes simply reflect deafferentation. To test this
possibility, we assessed retrosplenial function, as measured by zif268 and cytochrome oxidase,
following lesions of the mammillothalamic tract (MTT). This tract carries the unidirectional
projections from the mammillary bodies to the anterior thalamic nuclei and is important for
memory in both humans and rodents. The MTT lesions resulted in a marked decrease in zif268
expression in both deep and surperficial layers of retrosplenial granular b and dysgranular
cortex. Conversely, there was an increase in cytochrome oxidase activity in the superficial
layer of retrosplenial granular a and b following MTT lesions, which may reflect a compensatory
mechanism. These findings highlight the sensitivity of retrosplenial function to distal damage
and demonstrate that these effects are not simply a result of deafferentation. Furthermore,
the contrasting direction of changes when assessing two markers of neural activity
demonstrates that these modulations to retrosplenial function are more complex than
previously assumed.
(1) Cardiff University - United Kingdom
Milczarek Michal M | [email protected]
THE MODULATION EFFICIENCY OF PROCESSING OF VERBAL STIMULI IN
CONDITIONS OF LISTENING TO THE ACOUSTIC IMAGE OWN EEG
TEMPORAL REGIONS
Leonova, Maria (1) | Konstantinov, Konstantin (1)
The evaluation of reaction time to auditory verbal stimuli was performed before and after
listening to the acoustic image own EEG temporal areas to the right and the left.
There were 38 right-handed volunteers, 16 men and 22 women aged 19 - 37 years old. In the
first group (“T3”), 11 persons listened to the acoustic image own EEG left temporal area (T3)
in the real-time. In the second group (“T4”), 12 persons listened to the acoustic image own EEG
right temporal area (T4) in the real-time. In the third group (“control”), 15 persons listened to
records of acoustic image EEG made before during work with another respondent.
Transformations of EEG were being made by means of computer. The main thing there was an
agreement between the values of the duration periods of EEG waves with a set of sound samples.
Sound was presented binaurally via headphones, eyes closed. The procedure duration was 20
minutes.
Before and after the procedure the sensorimotor testing for every respondent took place
(reaction time was being estimated). In the test “acoustic words” the names of animals and
birds (active incentive) were represented via headphones in random order with the equal
probability. The time between the incentives was 1000 milliseconds. 110 occurrences were
offered. The mean value of reaction time on active incentives was estimated.
In the "control" group significant changes in reaction time is not registered: before the
procedure 742,1±58,8 ms, after the procedure 726,5±81,9 ms. In the “T3” group the reaction
time decreased from 747,3±48,1 ms to 717,6±38,2 ms (p<=0,01). In the “T4” group the reaction
time hadn’t been changed: before the procedure 756,6±85,8 ms, after the procedure
725,9±66,8 ms.
It can be concluded that increasing of functional activity occurs in those areas of the brain with
EEG which formed the acoustic image are presented in real time.
(1) Institute of Experimental Medicine - Russia
Leonova Maria | [email protected]
MATERNAL EXPOSURE TO ENVIRONMENTAL ENRICHMENT BEFORE AND
DURING GESTATION INFLUENCES BEHAVIOUR OF RAT OFFSPRING IN A SEX
SPECIFIC MANNER
Zinni, Manuela (1) | Zuena, Anna Rita (1) | Giuli, Chiara (1) | Cinque, Carlo (1,2) | Alemà,
Giovanni Sebastiano (1) | Giuliani, Alessandro (3) | Catalani, Assia (1) | Casolini, Paola (1) |
Cozzolino, Roberto (2) |
The beneficial effects of environmental enrichment (EE) applied immediately after weaning or
even in adulthood have been widely demonstrated. Little is known about the possible changes
in behaviour and brain development of the progeny following exposure of dams to EE. In order
to further investigate this matter, female rats were reared in EE for 12 weeks, from weaning
until a few days before delivery. To test the possibility that changes in offspring behaviour are
mediated by changes in their dam’s behaviour, prior to mating, the female rats were tested in
the Morris Water Maze (MWM) and in the Elevated Plus Maze (EPM). Maternal behaviour, during
the first days of lactation was also observed. Male and female offspring at different ages were
tested in play behaviour, learning, anxiety and social hierarchy. EE in the form of physical and
social interaction influenced the behavioural profile of the mother. Specifically, EE exposure
improved spatial learning ability and didn’t modify anxiety-like behaviour. Moreover, EE
mothers showed a decreased frequency of total nursing and a slight increase of licking behavior.
As for the effects on the offspring, maternal exposure to EE affected their behaviour in a sex
specific manner: increased social play behavior and anxiety-like behavior in males but not in
females; improved learning ability only in females; no effect on social hierarchy on both sexes.
Interestingly, maternal EE seemed to have a great influence on motility in male and female
offspring since we observed increased locomotor activity in the EPM and swimming speed in the
MWM. Overall, this study highlights the importance of environmental stimulation not only in the
animals for whom EE was provided but also to their future progeny.
This study was supported by the Fondazione Ethoikos.
(1) Department Physiology and Pharmacology - Sapienza University of Rome - Rome - Italy | (2)
Fondazione Ethoikos - Radicondoli - Italy | (3) Environment and Health Department - Istituto Superiore
di Sanità - Rome - Italy
Manuela Zinni | [email protected]
DEVELOPMENT OF THE MAM MODEL OF SCHIZOPHRENIA IN MICE:
ADAPTATIONS IN PREFRONTAL CORTICAL SYNAPTIC PLASTICITY
Sidiropoulou, Kyriaki | Chalkiadaki, Kleanthi (1) | Konstantoudaki, Xanthippi | Lambraki,
Kalliopi (1) | Foinikianaki, Emmanouela (1) |
Schizophrenia is a very complex, psychotic disease with neurobiological etiology. However, the
leading theory of its etiopathology is the neurodevelopmental hypothesis, which supports the
notion that genetic and/or toxic events during gestation disturb the normal development of the
nervous system. A well characterized animal model in rats based on this hypothesis is the
neurodevelopmental MAM model, generated by the administration of the DNA methylating
mitotoxin, methylazoxymethanol acetate (MAM), in pregnant rats on gestation day (GD) 17. The
offspring show core behavioral, histological and neurochemical phenotypes of schizophrenia.
Our aim is to establish the MAM model in mice, by injecting pregnant mice with MAM on GD16
or 17. MAM-exposed mice and their control littermates (saline-exposed) are examined during
adulthood. Our results showed that at the behavioral level, MAM-exposed mice presented
enhanced hyperlocomotion after acute administration of the NMDA receptor antagonist MK-801
(0.2mg/kg), while sensorimotor gating was found decreased, when measuring the prepulse
inhibition of the acoustic startle reflex. Furthermore, histological analysis revealed that MAMexposed mice seem to have decreased number of Parvalbumin-expressing interneurons in their
Prefrontal cortex (PFC), as well as thinning of the prefrontal cortex. In addition,
electrophysiological recordings from PFC showed alterations in the basal synaptic response and
in long-term potentiation in MAM-exposed mice, which correlates with decreased dendritic
spine density. Therefore, we have seen that mice prenatally exposed to MAM reproduce
abnormalities that model some aspects of schizophrenia. In addition, we find a combination of
synaptic plasticity and dendritic morphology deficits in the PFC that could underlie
schizophrenia-like cognitive deficits in this mouse model. Given the great variety of transgenic
animal models that exist, establishment of the MAM model in mice would allow the study of
different genetic backgrounds combined with the neurodevelopmental etiology, offering
possibly a valuable tool in schizophrenia research in the future.
This study was supported by a NARSAD young investigator award.
(1) University of Crete - Greece
[email protected] | [email protected] |
Sidiropoulou Kyriaki | [email protected]
SYNAPTIC ALTERATIONS IN THE PREFRONTAL CORTEX AND THE
HIPPOCAMPUS MEDIATE THE EFFECT OF WORKING MEMORY TRAINING IN
MICE
Sidiropoulou, Kyriaki (1) | Ioakimidis, Vasilis (1) | Konstantoudaki, Xanthippi |
Cognitive impairment is a core feature for both neurodegenerative diseases and normal ageing.
Even mild cognitive impairments interfere with day-to-day activities and decrease the quality
of life. As drug medications minimally improve cognition, cognitive therapies have received
great attention. Working memory training (WMT) has been suggested to improve not only
working memory per se, but also other cognitive functions, such as spatial memory, a property
known as ‘transfer’. Our aim is to study the effect of WMT in adult mice, both at the behavioural
and physiological level, in order to identify a neurophysiological substrate for the effects of
WMT.
We examined spatial memory recall and reversal learning in mice that were exposed to either
an adaptive delayed alternation task or the alternation task (with no delays) in the T-maze, as
well as, in naïve mice. First, mice were trained on the left-right discrimination task. Secondly,
mice were split into three groups: a) mice trained on the delayed alternation task with
increasing delays (adaptive WMT), b) mice trained on the alternation task (no delays), c) naïve
mice. Finally, mice were tested on their ability to recall the left-right discrimination and
reversal learning. Two to four days later, we performed electrophysiological recordings in
prefrontal cortex and hippocampus. Our results show that behaviourally, adaptive WMT
improves both spatial memory and reversal learning, while our electrophysiological recordings
revealed that it enhances long-term potentiation in both areas examined, possibly underlying
the cognitive improvement.
We found that WMT can improve other cognitive functions and the underlying synaptic plasticity
in key brain regions. Furthermore, we show that WMT not only improves behaviour but also
neuronal physiology. These results offer a foundation for further studies that could be used for
better design of effective cognitive therapeutic approaches applied on the research of both
ageing and neurodegenerative disease.
ANXIOLYTIC EFFECTS OF ENVIRONMENTAL ENRICHMENT ARE MEDIATED
BY NEUROPEPTIDE Y
Reichmann, Florian (1) | Hassan, Ahmed, M (1) | Herzog, Herbert (2) | Holzer, Peter (1)
Environmental enrichment (EE), a means to improve rodent housing and welfare, has
anxiolytic and stress-reducing effects in mice. Neuropeptide Y (NPY), a key peptide for the
processing of stress, has similar behavioural effects. Given these resemblances, the current
work assessed whether EE alters brain NPY expression and whether EE-induced behavioural
effects depend on NPY.
Introduction:
Wildtype (WT) and NPY knockout (NPY KO) mice housed either under standard
environment (SE) or EE were submitted to a behavioural battery consisting of the elevated plus
maze (EPM), open field test (OF), stress-induced hyperthermia (SIH) and forced swim test (FST)
after 9 weeks of differential housing. One day after the last behavioural test amygdalar and
hippocampal NPY levels were measured by PCR and ELISA.
Methods:
EE-housed WT mice made significantly more entries to the open arms of the EPM
compared to SE-housed WT mice, which indicates an anxiolytic effect of EE. Importantly, this
beneficial effect was not seen in NPY KOs. In contrast in the OF and the FST, NPY KOs showed
increased anxiety, reduced locomotor activity and depression-like behaviour independent of
housing conditions. Housing itself also affected FST behaviour as both EE-housed WTs and NPY
KOs spent more time climbing. The SIH suggested a negative effect of EE for NPY KOs but not
WT animals as only EE-housed NPY KOs had higher stress-induced rectal temperatures.
Molecular analysis of the WT brains revealed increased amygdalar and hippocampal NPY gene
expression but no change in the corresponding peptide levels suggesting higher NPY turnover in
EE-housed mice.
Results:
The current molecular and behavioural data favour the contention that NPY
contributes to the anxiolytic effects of EE. The absence of NPY abolishes this beneficial effect
and even induces negative effects in response to environmental stimulation.
Conclusion:
Research support: Supported by the Austrian Science Fund (FWF grant P 25912-B23).
(1) Medical University of Graz - Austria | (2) Garvan Institute of Medical Research - Australia
[email protected]
Reichmann Florian | [email protected]
LESIONS IN THE RETROSPLENIAL CORTEX IMPAIR STRATEGY SET-SHIFTING
BUT NOT REVERSAL LEARNING
Powell, Anna, L (1) | Nelson, Andrew, JD (1) | Vann, Seralynne, D (1) | Aggleton, John, P (1)
The retrosplenial cortex (RSC) appears to play an important role in spatial navigation and, in
particular, in switching between different spatial strategies. However, little is known about the
involvement of the RSC in strategy switching in non-navigational tasks. In order to examine the
role of the RSC in non-navigational cognitive flexibility, we used an automated operant task
that required rats to switch from a visual-cue to a response-based strategy. Sixteen Lister
Hooded rats with lesions in the RSC (and 11 surgical shams) were trained to lever-press for
sucrose pellet reinforcers based on a visual-cue (i.e. press the lever with light illuminated above
it). Then, once they had reached criterion performance, they were required to switch to using
a response-based strategy (e.g. always press the right lever). Finally, they experienced a simple
response reversal, whereby they were required to press the opposite lever to that on which
they were trained in the initial response-based training. The RSC-lesion group showed a greater
switch cost during the initial visual-to-response switch than sham animals, whist the opposite
was true for the simple response reversal. These data indicate the RSC may have a broader role
in cognitive flexibility which extends beyond the spatial domain.
(1) Cardiff Univeristy - Wales
Powell Anna L | [email protected]
ATTENTION DEFICIT AND IMPAIRED LEARNING OF ADULT MICE SUBJECTED
TO STRESS IN ADOLESCENCE
Lima, Ana Paula, N (1) | Reis-Silva, Thiago, M (1) | Sandini, Thaisa, M (1) | Massoco, Cristina,
O (1)
Adolescence is one of the critical periods of development and has a great importance to health
for an individual as an adult. Stressors or traumatic events during this period are associated
with numerous changes in the development and plasticity of the neuroendocrine system
predisposing the individual to psychiatric disorders as related to anxiety or depression. However
stress in adolescence is a very discussed topic, there are few studies about the long-term effects
of stress during this period. Therefore, this study aims to assess the impacts in adulthood of
unpredictable stress during adolescence. Thirty days old Balb/c male mice were subjected to
a random pattern of stressful situations twice daily for ten days. Twenty days after the end of
the stress protocol when animals are already adults, behavioural was evaluated. Blood and
brain were collected for analysis of plasma corticosterone and neurochemistry. The
experiments were performed in accordance with the guidelines of the Bioethical Committee on
Care and Use of Laboratory Animal Resources of the School of Veterinary Medicine, USP, Brazil
(protocol number 4485180614). Unpredictable stress shows that treatment increased locomotor
activity (p <= 0.05), impaired learning in novel object recognition task (p <= 0.05), affected
plasma levels of corticosterone (p <= 0.05), drecreased serotonergic activity on hippocampus
(p <= 0.05), hypothalamus (p <= 0.05), prefrontal cortex (p <= 0.05) and striatum (p <= 0.05)
and decreased noradrenergic activity on hippocampus (p <= 0.05) and hyphotalamus NOR (p <=
0.05). More studies are being done in order to better characterize this unpredictable stress
model and their consequences for adulthood.
(1) University of Sao Paulo - Brazil
[email protected]
Lima Ana Paula N | [email protected]
PATTERN AND PATH ENCODING: NEW TOOL FOR UNWELDING VISUOSPATIAL MEMORY THROUGH THE USE OF A SENSORIZED PLATFORM
Lupo, Michela (1,2) | Tedesco, Anna Maria (1,2) | Aloise, Fabio (3) | Ferlazzo, Fabio (1) |
Cardillo, Chiara (1) | Leggio, Maria (1,2)
It has been demonstrated that the processing of visuospatial information in reaching or
navigational space is supported by independent systems.
Moreover, it has been proposed that visuospatial information may require a pattern or a path
encoding. The pattern encoding is specifically used when the task requires a simultaneous
processing of spatial positions, while the path encoding is used in sequential processing that
allows to link different spatial positions in correct succession.
The aim of the present study was to disentangle these different components of visuospatial
information processing in navigational tasks by the development of an innovative sensorized
platform, and to verify if subjects use the same strategies when similar tasks are performed in
reaching space. We assessed the performance of 70 healthy volunteers on the sensorized
platform to investigate topographical orientation (route memory) in three different tasks that
required a sequential strategy (named Route A and Route B tasks, which differ for sequential
load required for their implementation) or a simultaneous strategy (named Simultaneous
Walking Test).
Subsequently, similar tasks were performed in reaching space, (by means Corsi Block tapping
Test and a Modified Corsi Test for the sequential strategy and Simultaneous Paper Test for the
simultaneous strategy).
The six tasks were submitted to factor analysis (Principal Axis Factoring). This analysis showed
four factors that explaining the 51.3% of the total variance: Corsi Block tapping Test (.501);
Simultaneous Paper and Walking Test (-.74 and -.51, respectively); Route A (-.38); Modified
Corsi Test and the Route B (.72 and .67, respectively). This clustering demonstrates that - the
sensorized platform, set up in the present study, allows to identify the different strategies
performed to correctly solve visuo-spatial tasks in navigational space - the same strategies can
be also used in reaching space according to the task demand.
(1) Department of Psychology - Sapienza University - Rome - Italy | (2) Ataxia Laboratory - IRCCS Santa
Lucia Foundation - Rome - Italy | (3) Alfameg s.r.l. - Rome - Italy
Lupo Michela | [email protected]
REINFORCING PROPERTIES OF METHOXETAMINE, A NOVEL KETAMINE-LIKE
COMPOUND: EFFECTS ON DOPAMINERGIC TRANSMISSION AND SELFADMINISTRATION IN RAT
Mutti, Anna (1) | Mancini, Laura (1) | Scherma, Maria (2) | Aroni, Sonia (2) | Padovani, Laura
(1) | Muntoni, AnnaLisa (2) | Fadda, Paola (2) | Fattore, Liana (3) | Chiamulera, Christian (1)
Recently, an increasing number of emergency cases due to a novel ketamine-like drug,
methoxetamine (MXE) were reported in several countries. However, little is known about the
neuropsychopharmacological and reinforcing profile of this compound. Our project aims to
characterize the reinforcing properties of MXE in comparison to ketamine. Since ketamine
exerts its effects by increasing dopamine neuron (DN) firing, dopamine release and maintains
self-administration (S/A) in rats, we hypothesize that MXE may own similar effects.
In vivo standard electrophysiological techniques have been performed in anaesthetized male
rats. The response to antidromic stimulation of mesolimbic DN in ventral tegmental area (VTA)
was recorded from terminal fields in nucleus accumbens (NAc) after acute 0.031,0.062,0.125
0.25 and 0.5 mg/Kg intravenous (IV) MXE. In vivo microdialysis was performed in freely moving
rats to evaluate the effects of acute MXE administration (0.125,0.25 and 0.5 mg/Kg IV) on
dopamine release in NAcShell. A ketamine self-administration substitution study was performed
in rats trained to self-administer IV ketamine. At responding stability, rats were exposed to
sequential phases of MXE substitution at different dosages (starting empirically from 0.5, then
decreasing to 0.250 and 0.125 mg/kg IV).
Acute MXE (0.03-0.5 mg/Kg IV) induced an increase of baseline firing rate of VTA DN projecting
to the NAc in a dose related manner with significance reached at 0.062 mg/Kg (p<=0.005). MXE
also significantly increased dopamine extracellular levels in NAcShell at both 0.5 and 0.25
mg/Kg, but at different time onset, respectively 40 min and 100 min (p<=0.05). IV MXE 0.125
and 0.25 mg/Kg, but not MXE 0.5, substituted for ketamine S/A. This study confirmed the
reinforcing effects of MXE as shown in the behavioural study and supported by
electrophysiological and neurochemical data.
[Funded by “Joint Project 2012” from University of Verona, in collaboration with C.N.R.
Institute of Neuroscience, Cagliari, and University of Cagliari].
(1) University of Verona - Italy | (2) University of Cagliari - Italy | (3) CNR Institute of Neuroscience
Cagliari - Italy
Mutti Anna | [email protected]
REVERSING EXCITATORY GABA SIGNALING RESTORES SYNAPTIC
PLASTICITY AND MEMORY IN A MOUSE MODEL OF DOWN SYNDROME
Parrini, Martina (1) | Deidda, Gabriele (1) | Naskar, Shovan (1) | Fernandez Bozarth, Ignacio
(1) | Contestabile, Andrea (1) | Cancedda, Laura (1)
Trisomic mouse models of Down syndrome (DS) reproduce the main cognitive disabilities of the
human syndrome. In particular, Ts65Dn mice show impaired synaptic plasticity as well as
learning and memory deficits. Increased GABAergic transmission through chloride-permeable
GABA-A receptors (GABAAR) has been shown to largely determine these deficits in DS mice.
However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here,
we show that GABAAR signaling is excitatory rather than inhibitory, and the reversal potential
for GABAAR-driven chloride currents (ECl) is shifted toward more positive potentials in the
hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation chloride cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1
inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and
hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABAAR
signaling is excitatory in adult DS mice and identify a new therapeutic approach for the
potential rescue of cognitive disabilities in individuals with DS.
(1) Department of Neuroscience and Brain Tecnologies - Fondazione Istituto Italiano di Tecnologia Italy
Parrini Martina | [email protected]
GRAVITY PERCEPTION BY VESTIBULAR SENSORS BUILDS MOTOR AND
COGNITIVE DEVELOPMENT: PERSPECTIVES IN PSYCHIATRIC DISEASES IN
CHILDREN
Le Gall, Anne (1) | Toulouse, Joseph (1,2) | Machado, Marie-Laure (1) | Hilber, Pascal (3) |
Besnard, Stéphane (1,4)
Designed to encode gravity level, linear acceleration and head movements, the vestibular sense
organ is classically associated with balance, posture and movement coordination. Additionally
this sense organ is involved in spatial cognition that requires (I) the vestibular cortex located
within temporal areas processing multisensory integration for three-dimensional body schemes
and verticality perception; and (II) the hippocampus processing visuo-vestibular integration
involved in spatial memory and navigation in humans, monkeys and rodents at adulthood. We
hypothesized that Earth gravity might, through the vestibular sense organ, more largely build
different aspects of cognition, emotion and social interaction from childhood as suggested by
psycho-behavioral reports in infants suffering from psychiatric diseases.
In this way we studied an original KO Het mice model selectively devoid of otoconia in the inner
ear i.e. with no gravitational vestibular perception. Behavioral performances were assessed by
a set of motor, cognitive and emotional tests from birth to adulthood in Het mice compared to
a control group. NMDA receptors density supporting neuronal plasticity was investigated at the
same time by autoradiographic measurements in multisensory brain areas whose hippocampus.
A developmental delay maximal at P7/P8 was reported in young Het mice, delay not
counterbalanced by early tactile sensitive postnatal stimulation. If balance was logically
impaired at adulthood, hyperactivity with stereotyped behavior and repetitive tasks was more
interestingly noticed. Anxiety level was less pronounced in adult Het mice while social
interaction was impaired. We observed that Het mice seemed to oscillate between autism
spectrum disorders and hyperactivity syndrome. These relevant behavioral aspects were
correlated with NMDA receptors modulation in multisensory integration areas. We highlight for
the first time that vestibular perception related to gravity shapes cognitive, emotional and
social developmental aspects. The vestibular sensory approach from an otoconia-deficient
rodent model offers perspectives in physiopathology and therapy in child psychiatric diseases.
(1) University of Caen - INSERM U1075 COMETE - France | (2) Department of pediatrics neurology CHU of Caen - France | (3) University of Rouen - EA 4700 PSY-NCA - France | (4) Department of
neurophysiology - CHU of Caen - France
Le Gall Anne | [email protected]
EFFECTS OF ADIPOKINETIC HORMONES ON NEUROGENESIS AND
NEURODEGENERATION
Köktürk, Sibel (1) | Mutlu, Oguz (2) | Akar, Furuzan (2) | Ulak, Guner | Erden, Faruk |
Celikyurt, Ipek, K
Adipokinetic hormones (AKHs) are typical stress peptides found in insects that regulate
metabolic responses to stress by stimulating catabolic reactions and mobilizing energy stores.
Insect anti-stress responses, including those induced by insecticides, are controlled by AKHs.
AKHs are predominantly associated with intrinsic neurosecretory cells of the corpora cardiaca
(CC) of insects. However, presence of AKHs had also been reported a small number of cells
within the brain.
Adult hippocampal neurogenesis is the process whereby adult neural precursor cells increase in
the subgranular zone (SGZ) of the dentate gyrus (DG). The aim of this study was to investigate
the effects of Anax imperator AKH (Ani-AKH) (2 mg/kg), Libellula auripennis AKH (Lia-AKH) (2
mg/kg) and Phormia-Terra hormone (Pht-HrTH) (2 mg/kg) administered for 14 days on
neurogenesis and neurodegeneration in DG of the hippocampus in the brain of naive mice,
using bromodeoxyuridine (BrdU) immunohistochemistry and Hematoxylin-eosin (H&E) stainings.
Mice were intraperitoneally injected with BrdU (50 mg/kg) and were killed 24 hours later.
Hippocampal sections were collected and processed for BrdU immunohistochemistry and H&E
stainings. BrdU labeled cells in the DG were then counted, and compared to determine the
degree of neurogenesis.
Our results showed that Pht-HrTH and Ani-AKH groups significantly increased the number of
BrdU labeled cells while Lia-AKH group decreased than the sham group in the DG.
Neurodegeneration was lower in the Pht-HrTH group than in the Ani-AKH and Lia-AKH groups.
Our findings suggest that AKHs have potential proliferative and neuroprotective effects in
hippocampal neurogenesis and neurodegeneration.
(1) Department of Histology and Embriyology - Medical Faculty - Ordu University - Ordu - Turkey | (2)
Department of Medical Pharmacology - Psychopharmacology Lab. - Medical Faculty - Kocaeli University
- Kocaeli - Turkey
NEURONAL ENSEMBLE CHARACTERISATION FOLLOWING EXPOSURE TO
FOOD-ASSOCIATED CUES
Sabine, Hessler (1) | Joseph, J, Ziminski (1) | Meike Claudia, Sieburg (1) | Gabriella,
Margetts-Smith (1) | Eisuke, Koya (1)
Learned associations between natural rewards and the environmental cues that predict their
availability are encoded by a minority of sparsely distributed, behaviourally activated neurons,
called 'neuronal ensembles'. Alterations in intrinsic membrane properties and at the glutamate
synapse play an important role in many learning and memory processes. Yet, to date very little
is known about these alterations specifically on these neurons that encode this type of
association. The aims of our laboratory are to identify neuronal ensembles activated by
environmental cues associated with sucrose in corticostriatal brain areas and to characterise
their physiology at glutamate synapses and their intrinsic membrane properties.
To that end, we measured conditioned behavioural and neuronal ensemble activity (using GFP
immunohistochemistry) using Fos-GFP mice that express GFP in strongly activated neurons. We
trained these mice to associate an auditory cue with non-contingent sucrose delivery following
multiple training sessions. Five to seven days following conditioning, sucrose cue exposure
elicited conditioned approach towards the sucrose delivery site and enhanced ensemble activity
in the orbitofrontal cortex and nucleus accumbens. These data suggest that neuronal ensembles
that encode sucrose memories reside in these areas. Investigations are underway into
characterizing the membrane properties in these activated neurons using Fos-GFP mice.
Sabine Hessler, Joseph J. Ziminski, Meike Claudia Sieburg, Gabriella Margetts-Smith, Eisuke
Koya
Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, BN1 9QG, United
Kingdom
(1) University of Sussex
| [email protected]
Sabine Hessler | [email protected]
HISTONE ACETYLATION MEDIATES THE INFLUENCE OF SOCIAL DEFEAT IN
THE REWARDING EFFECTS OF COCAINE IN THE CPP
Rodríguez-Arias, Marta (1) | Montagud-Romero, Sandra (1) | Blanco-Gandía, M. Carmen (1) |
Navarro-Francés, Concepción, I (1) | Arenas, M Carmen (1) | MIñarro, Jose (1)
Recent studies have observed chromatin remodeling at specify gene promoter regions related
with social defeat. This kind of stress has been associated with induction of histone acetylation
through modulation of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity.
The aim of the present study was to evaluate the implication of inhibitors of HAT and HDAC in
the effects of social defeat on the conditioning rewarding effects of cocaine. A total of 100
adult male mice of the OF1 strain were exposed to four episodes of repeated social defeat
(RSD) lasting 25 min each. Thirty minutes before each episode, saline, HAT (curcumin 50 and
100mg/Kg) or HDAC (valproic acid 250 and 500mg/Kg) inhibitors were administered. Each
episode consisted of three phases that began by placing the experimental animal (which was
protected by a mesh) in the home cage of the aggressive opponent for 10 min. In the second
phase, the wire mesh was removed from the cage and a 5 min period of confrontation initiated.
In the third phase, the wire mesh was replaced for a further 10 minutes to allow social threat
from the resident. The exploration group underwent the same social stress protocol, but
without the presence of a “resident” mouse in the cage. Conditioned place preference (CPP)
took place three weeks after the last social defeat. Our results showed that RSD saline-treated
mice developed CPP, and that this preference was reinstated by a priming dose of cocaine.
Administration of curcumin 100mg/kg blocked preference, while valproic acid did not block
preference. Our results indicate that inhibition of HAT blocks RSD-induced increases in the
conditioned rewarding effects of cocaine.
Acknowledgements: Instituto de Salud Carlos III, (RTA) RD12/0028/0005 and
Unión Europea, Fondos FEDER “una manera de hacer Europa”. Delegación del Gobierno para
el Plan Nacional Sobre Drogas, 2014I007. Generalitat Valenciana, PROMETEOII/2014/063
Rodríguez-Arias Marta | [email protected]
DIAMINOPHENOTHIAZINE REVERSES COGNITIVE DEFICITS IN TAU
TRANSGENIC MICE
Melis, Valeria (1,3) | Harrington, Charles, R. (2,3) | Wischik, Claude, M. (2,3) | Riedel,
Gernot (1)
Alzheimer’s disease (AD) is recognised as the most common neurodegenerative disease for
which the abnormal aggregation of the protein tau is a key pathological hallmark. Transgenic
mice expressing abnormal tau represent an invaluable tool for elucidating the mechanisms
leading to neurodegeneration and especially, for the evaluation of potential therapeutic
compounds.
Several compounds aimed to prevent and/or inhibit tau fibril formation have been identified
and hold considerable promise for the treatment of tau-related neurodegenerative diseases. In
particular, methylthioninium (MT) acts as an inhibitor of tau aggregation in vitro and in vivo
whether administered as chloride salt (MTC) or in the reduced leuco-MT form (LMTX®). LMTX®
is now been investigated in phase 3 clinical trials.
In this study, we examined the effects of another diaminophenothiazine (1,9-diethylthioninium
nitrate; ETN) on cognitive and motor deficits in two tau transgenic mouse models: Line 1, in
which a truncated fragment of human tau (AA 296-390) is overexpressed and Line 36 expressing
the full-length human tau isoform containing P301S and G335D mutations. Line 1 mice present
with cognitive impairments detected in two different open field water maze paradigms and
Line 36 are characterized by motor deficits revealed in the RotaRod task.
Oral administration of ETN for 14 days (2-, 5- and 15-mg/kg) was effective in reversing the
motor phenotype in Line 36 mice. Improvements in motor learning seen in all doses were
particularly strong for 5 and 15mg/kg cohorts. Furthermore, treatment with ETN (5 mg/kg daily
for up to 8 weeks) was able to ameliorate spatial deficits in Line 1 mice in both a standard
reference memory and a problem-solving task in the water maze; transgenic animals achieved
performance comparable to that of wild-type mice.
These findings further support the use of diaminophenothiazines in the treatment of cognitive
symptoms of AD and tau-related disorders.
(1) School of Medical Sciences - University of Aberdeen - Aberdeen - UK | (3) TauRx Therapeutics Ltd Singapore | (2) School of Medicine and Dentistry - University of Aberdeen - Aberdeen - UK
[email protected]
Melis Valeria | [email protected]
WITHDRAWAL AFTER CHRONIC CONTINUOUS ACCESS TO A HIGH-FAT
DIET DURING ADOLESCENCE: CROSS-SENSITIZATION AND VULNERABILITY
TO THE REWARDING EFFECTS OF COCAINE.
Miñarro, Jose (1) | Blanco-Gandía, Carmen, M (1) | Montagud-Romero, Sandra (1) | MateosGarcia Ana (1) | Aguilar, María, A (1) | Rodríguez-Arias, Marta (1)
Overeating and obesity are major problems in today’s society, especially in adolescents.
Preclinical studies have provided evidence that free access to high-fat diets have serious effects
on the brain reward system and prolonged exposure to palatable food can lead to dependencelike symptoms. The aim of this study was to evaluate the effects of withdrawal following
continuous access to a high-fat diet during adolescence on anxiety levels, cocaine-induced
Conditioned Place Preference (CPP) and locomotor cross-sensitization. A total of 90 adolescent
male mice of the OF1 strain (PND 29) were assigned either standard or continuous access to a
high-fat diet. The following experimental groups were included (n=15): Control (standard diet
during the whole procedure); High-fat (high-fat diet during the whole procedure); and High-fat
15w (high-fat diet until 15 days before CPP). CPP induced by a subthreshold dose of cocaine (1
mg/kg) took place on PND 69 and anxiety was assessed in the Elevated Plus Maze (EPM) on PND
84 (15 day withdrawal). Cross-sensitization with 10mg/kg cocaine took place in 45 cocainenaïve animals distributed among the same 3 groups.Results revealed that only the High-fat 15w
group developed preference for the drug-paired compartment, which was reinstated after
extinction. Cross-sensitization data showed a significant increase of locomotor activity with
respect to the drug-free period in the same group. Results obtained in the EPM also confirmed
a higher level of anxiety in the withdrawal group. We propose that withdrawal from a palatable
food is a gateway to the development of addiction.
Aknowledgements: Instituto de Salud Carlos III, (RTA) RD12/0028/0005 and
Unión Europea, Fondos FEDER “una manera de hacer Europa”. Delegación del Gobierno para el
Plan Nacional Sobre Drogas, Proyectos de Investigación sobre Drogodependencias, 2014I007.
Generalitat Valenciana, PROMETEOII/2014/063.
| [email protected] | [email protected]
Miñarro Jose | [email protected]
CAN CANNABIS DAMPEN THE TOXIC EFFECTS OF ALCOHOL ON THE
LETTER-NUMBER SEQUENCING SUBTEST OF WORKING MEMORY?
Vinader-Caerols, Concepción (1) | Duque, Aránzazu (1) | Monleón, Santiago (1)
Adolescence (from 10 to 19 years; WHO, 1986) is a critical stage of development corresponding
to the transition from childhood to adulthood, and is characterized by a wide variety of
physiological and psychological changes. Adolescents develop risk behaviours, such as alcohol
binge drinking (BD), alone or in polydrug use with cannabis (94.4% of Spanish cannabis users
consume it together with alcohol). This polydrug use can be especially toxic for brain
development, but no study has investigated the effects of Cannabis-BD on memory in teenagers.
The present study evaluates the effects of a history of BD alcohol consumption, alone or with
cannabis, on the letter-number sequencing subtest of Working Memory (WM) (Wechsler Memory
Scale) in adolescents. Subjects were 18-19 years old (n = 97; 40 men and 57 women). Along
with other inclusion and exclusion criteria, AUDIT and CAST tests (for dependence of alcohol
and cannabis, respectively) were employed for the subjects’ selection. In each sex, subjects
were assigned to one of three experimental conditions taking into account their History of
Drinking: 1) Refrainers; 2) Binge Drinkers; and 3) Cannabis-BD consumers. Subjects performed
the letter-number sequencing subtest of WM. Results showed that Cannabis-BD consumers
performed significantly better than subjects with a BD history. Furthermore, men performed
better than women in this test. Though therapeutic effects of cannabis have been reported,
we believe that the recreational use of cannabis with alcohol is toxic for the adolescent brain
development. However, our results suggest that cannabis dampens the toxic effects of alcohol
on letter-number sequencing recall of WM. These results should be interpreted with caution
and investigated more thoroughly.
Vinader-Caerols Concepción | [email protected]
CHOLINERGIC AND NMDA SYSTEMS INVOLVED IN FORMATION AND
RECOMBINATION OF CROSS-MODAL ASSOCIATIONS IN THE LATERAL
ENTORHINAL CORTEX AND THE DORSAL HIPPOCAMPUS
Boisselier, lise (1) | Ferry, Barbara (1) | Gervais, Remi (1)
Even though olfaction and touch are two essential sensory modalities for object exploration,
cross-modal olfactory-tactile (OT) learning and memory processes in behaving animal are still
poorly understood. The present study was aimed at characterizing the neurobiological substrate
involved in the associative processes underlying acquisition and recombination (acquisition with
familiar items) of OT learning. To this aim, freely moving rats bilaterally implanted in the
lateral entorhinal cortex (LEC) or in the dorsal hippocampus (DH) received d-APV (NMDA
antagonist) or scopolamine (cholinergic antagonist) just before the different phases of a new
developed OT task consisting in finding one baited cup among three, each of the cups presenting
a different odor/texture combination. The results showed that NMDA receptor blockade in the
LEC induced a deficit in the OT acquisition and recombination tasks but this deficit was only
partially observed with scopolamine. In contrast, only scopolamine infusion in the DH induced
a deficit in the OT recombination. Moreover, four control groups of rats infused with lidocaine
in LEC or DH revealed no deficit in acquisition and recombination of unimodal olfactory and
tactile tasks. Taken together, our data suggest that the LEC is involved in the formation of OT
representations (regardless of new or familiar items) through an NMDA glutamatergic and
partially cholinergic process. In contrast, muscarinic system of the DH is critical in the process
underlying the OT recombination process that could involve a feedback from the DH to the LEC
which is involved in the formation of OT associations. These data suggest a network model
according to which learning and memory of OT association processes are supported by a
functional interaction between the LEC and the DH.
(1) Lyon Neuroscience Research Center - CNRS UMR 5292 INSERM U 1028 - Université. Claude Bernard
- Lyon 1
Boisselier Lise | [email protected]
EXPLORATORY STRATEGIES IN THE MULTIVARIATE CONCENTRIC SQUARE
FIELD(TM) TEST IN ADOLESCENT MALE RATS AND ASSOCIATIONS TO
SOCIAL PLAY BEHAVIOR
Lundberg, Stina (1) | Högman, Cecilia (1) | Roman, Erika (1)
In the present study associations between behavioral strategies in the multivariate concentric
square fieldTM (MSCF) test and social play behavior (SPB) were investigated as part
of the validation of the MCSF test for adolescent rats. Outbred male Wistar rats were tested in
week five and six of life and the order of the tests were counterbalanced. Only one of the over
sixty parameters recorded differed between the animals that performed the tests in different
order. Measurements of general and exploratory activity in the MCSF showed positive
correlations to measurements of social activity in the SPB test. Risk assessment behaviors in
the MCSF, on the other hand, showed negative correlations with the frequency of social activity
in the SPB test. Measurements of shelter seeking in the MCSF showed negative correlations to
social activity and the amount of received play behavior in the SPB test. The latency to initiate
play was however positively correlated to measurements of shelter seeking. A classification
based upon shelter seeking showed that rats displaying high levels of shelter seeking in the
MCSF exhibited lower levels of play in the SPB test and they were more reluctant to initiate
play. In the MCSF test high shelter seeking animals displayed a tendency to be less risk taking
than the low shelter seekers while the activity remained the same. Repeated testing in the
MCSF test and associations to other common behavioral tests will complement these results and
contribute to the validation of the MCSF test for adolescent rats.
(1) Department of Pharmaceutical Biosciences - Uppsala University - Sweden
Lundberg Stina | [email protected]
GENETIC-DRIVEN PARTIAL REDUCTION OF THE DOPAMINE TRANSPORTER
(DAT) IN MICE PRODUCES ADHD- BUT NOT SCHIZOPHRENIA-RELEVANT
BEHAVIORAL PHENOTYPES
Mereu, Maddalena (1)
Attention deficit hyperactivity disorder (ADHD) and schizophrenia are psychiatric disorders with
a strong genetic component. The neuropathophysiology of both diseases share alterations in
the dopaminergic system, however, it is not yet clear how genetic variations influencing the
dopaminergic system might differentially give rise to ADHD or schizophrenia. Indeed, while
sharing common features (e.g. some cognitive deficits), these two diseases have distinctive
peculiar phenotypes: ADHD behavioral alterations are more pronounced earlier in life while the
opposite is true for schizophrenia, hyperactivity is more evident in ADHD while sensorimotor
gating deficits are more consistently found in schizophrenia, psychostimulants ameliorate the
symptomatology in ADHD while exacerbate it in schizophrenia. The dopamine transporter (DAT)
is the major player in the clearance of extracellular dopamine in the striatum and has been
suggested as a potential susceptibility gene involved in both ADHD and schizophrenia. Mice
lacking the DAT (-/-) have been extensively studied. However, DAT-/- mice present extreme
phenotypes more relevant to the DAT deficiency syndrome (early Parkinson’s disease). To
better mimic human conditions possibly relevant to ADHD and/or schizophrenia, we used mice
carrying a partial reduction of DAT (i.e. DAT+/-) to investigate how this genetic mutation may
contribute to the development of these two psychiatric disorders. These mice were then
assessed for behavioral phenotypes relevant to ADHD and/or schizophrenia neuropathology
from infancy to adulthood, using different behavioral tasks such as Prepulse Inhibition,
Locomotor Activity and Temporal Order Object Recognition. DAT +/- mice exhibited an early
appearance of increased levels of locomotor activity that could be reverted by amphetamine
treatments. In contrast, sensorimotor gating abilities measured with prepulse inhibition of
acoustic stimuli were normal throughout the development. Our findings highlight how DAT
genetic mutations might be more relevant to ADHD rather than schizophrenia and establish the
DAT+/- mutant mice as a valid experimental model of ADHD.
(1) IRCRR MEDEA University of Padova Italy
Maddalena Mereu | [email protected]
ALLODYNIA IN CALBINDIN AND PARVALBUMIN KNOCKOUT MICE AFTER
SCIATIC NERVE CHRONIC CONSTRICTION INJURY
Slugocka Anna (1, 2) | Adamczyk Waclaw (1, 3) | Golyszny Milosz (1) | Ludyga Tomasz (1) |
Lysien Anna (1) | Grabowska Marta (1, 2) | Barski Jaroslaw-Jerzy (1, 2)
Calbindin and parvalbumin are intracellular calcium binding proteins widely distributed in
muscle fibers and GABA-ergic inhibitory neurons and interneurons. Recent investigations have
shown a relationship between the insufficient activity of those neurons and common
neurological diseases such as Alzheimer disease, autism, schizophrenia and ataxia. There is
little known about mechanism by which calbindin or parvalbumin knockouts have increased pain
threshold. The aim of the study was to shed light on mechanism of neuropathic pain and role
of calbindin and parvalbumin in central nervous system. We examined not only single mutants
but also double knockout mice for both proteins. In our study we checked mechanically and
thermally induced allodynia under conditions of neuropathic pain caused by chronic constriction
injury.
(1) Center for Experimental Medicine Medical University of Silesia - Poland | (3) The Jerzy Kukuczka
Academy of Physical Education in Katowice | (2) Department of Physiology Medical University of
Silesia - Poland
Slugocka Anna | [email protected]
MODIFICATION OF KETOGENIC DIET ABOLISHES ITS DEBILITATING EFFECT
IN MICE
Slugocka Anna (1, 2) | Liskiewicz Arkadiusz (2) | Grabowska Marta (1, 2) | Wiaderkiewicz Jan
(1, 2) | Barski Jaroslaw-Jerzy (1, 2)
High fat and low carbohydrate ketogenic diets (HFKD) are used in many studies in rodents.
There is however only little known about the impact of HFKD on animal welfare. Our earlier
data showed that HFKD has a detrimental effect on animal development with special impact on
growth of young mice and rats. Here, we used a classical HFKD (cHFKD) prepared analogically
to the commercially used formula and a modified HFKD (mHFKD). C57BL/6 mice were fed with
the standard and modified diet from day 20 postpartum for one month, and both groups were
analyzed by means of Rotarod test, strength grip test and open field test. To assess the
influence of both diets on neurons, cerebellar Purkinje cells were visualized and counted by
means of immunohistochemical staining. Obtained results showed that the use of the cHFKD
results in retardation in many aspects of development but improvement of the diet formula is
able to abolish the negative side effects. In contrast to animals on cHFKD, mice fed with mHFKD
did not show growth inhibition, decrease in muscle strength or behavioral disturbances.
(1) Center for Experimental Medicine Medical University of Silesia - Poland | (2) Department of
Physiology - Medical University of Silesia - Katowice - Poland
Slugocka Anna | [email protected]
IMPULSIVITY AND ITS RELATIONSHIP TO ATTENTIONAL BIAS IN SMOKERS
Shepherd, Therese, E. (1) | Kolokotroni, Katerina, Z. (1) | Selby, Danielle, L. (1) | Fisher,
Katie (1) | Harrison, Amanda, A (2)
Key theories identify the roles of both attentional bias and impulsivity in addictive behaviours.
Despite this, research has not yet provided an in-depth analysis of how components of trait and
behavioural impulsivity may relate to bias towards drug-cues at different stages of attentional
processing. This study explored these potential relationships in cigarette smokers who differed
in dependency and deprivation.
Non-smokers (n=26), light satiated smokers (<=5 cigs/day, n=25), heavy satiated smokers (≥10
cigs/day, n=23) and heavy 12 hour deprived smokers (n=30) completed the Barratt Impulsivity
Scale, a hypothetical monetary Delayed Discounting Task, an Information Sampling Task (IST)
and a Visual Dot-Probe assessing initial orientation towards (200ms exposure) and delayed
disengagement from (2000ms) smoking-related cues.
Light smokers showed an attentional bias at 2000ms only, while for heavy satiated smokers,
there was evidence of a bias at both 200ms and 2000ms. All smokers reported significantly
higher motor trait impulsivity than non-smokers, while higher non-planning and attentional
impulsivity was evident amongst heavy smokers only. In the IST, heavy deprived smokers
sampled information to a significantly lower degree of certainty before making decisions than
satiated heavy smokers and non-smokers. In contrast, significantly more pronounced
discounting of delayed rewards was evident in heavy satiated smokers relative to deprived and
non-smokers. No associations were found between attentional bias to smoking-related cues
and trait or behavioural dimensions of impulsivity.
Delayed disengagement to drug cues characterises both heavy and light satiated smokers. The
transition to dependency is associated with the additional emergence of attentional bias at
initial orientation. Nicotine deprivation appears to have contrasting effects on components of
behavioural impulsivity, being associated with risky judgements but normal discounting of
delayed rewards. In the case of nicotine addiction, strong associations do not appear to exist
between impulsivity and attentional bias, suggesting they may have independent roles in the
addiction cycle.
(1) Faculty of Health and Social Sciences - Leeds Beckett University - England | (2) Institute of
Psychological Sciences - University of Leeds - England
Shepherd Therese E. | [email protected]
DOUBLE DISSOCIATION IN THE ROLE OF THE BASOLATERAL AMYGDALA
AND THE INSULAR CORTEX IN THE ACQUISITION AND PERFORMANCE OF
GOAL-DIRECTED ACTIONS
Parkes, Shauna, L (1) | Ferreira, Guillaume (1) | Coutureau, Etienne (2)
Choice between goal-directed actions requires both knowledge of the relationship between
actions and their consequences and the ability to compare those consequences on the basis of
their current value. Recent evidence indicates that the basolateral amygdala (BLA) and the
insular cortex (IC) play a critical role in goal-directed behavior, however the precise role of
these regions in the acquisition versus performance of goal-directed actions remains unknown.
Here, we used a pharmacogenetic approach, the DREADD (designer receptors exclusively
activated by a designer drug), to inhibit neuronal activity in the BLA or the IC selectively during
the acquisition or the performance of goal-directed actions. Rats first received stereotaxic
injection of an adeno-associated virus expression system carrying the inhibitory hM4Di designer
receptor (AAV8-CaMKIIa-hM4Di-mcherry) into either the BLA or the IC. Following recovery, rats
were trained to press two levers for two distinct outcomes after which one of the outcomes
was devalued by sensory specific satiety immediately prior to a choice extinction test. Rats
were injected with either the hM4Di specific agonist clozapine-N-oxide (CNO; 1 mg/kg) or saline
either before training or before the choice test. BLA inhibition prior to training, but not prior
to test, abolished selective devaluation. In contrast, IC inhibition before test, but not prior to
training, disrupted outcome devaluation. These results suggest a double dissociation in the role
of the BLA and the IC in the acquisition and performance of goal-directed actions. Specifically,
the BLA, but not the IC, is required for learning specific action-outcome associations whereas
the IC, but not the BLA, is necessary for the performance of goal-directed actions based on the
current incentive value of their outcomes.
(1) Nutrition et Neurobiologie Intégrée - UMR 1286 - INRA - Université de Bordeaux - France | (2)
INCIA - UMR 5287 - CNRS - Université de Bordeaux - France
Parkes Shauna L. | [email protected]
LONG TERM IMPACT OF SUCROSE OVERCONSUMPTION AT ADOLESCENCE
ON HEDONIC AND MOTIVATIONAL SYSTEMS
Naneix, Fabien (1) | Darlot, Florence (1) | Pape, Jean-Remi (1) | Coutureau, Etienne (1) |
Cador, Martine (1)
Adolescence represents a critical period characterized by major neurobiological changes which
allow the transition into adulthood. However, this brain immaturity also constitutes a
vulnerability window to external insults. For instance, adolescents are more sensitive to
rewarding effects of palatable food, but the long term impact of the (over)consumption of
these rewards remains poorly understood. Recently we have reported that adolescent
overconsumption of sweet rewards induces motivational deficits for sweet food at adulthood.
Based on this, we hypothesize that adolescent diet could alter reward system involved in the
processing of hedonic and motivational properties of food.
Adolescent rats were given free and continuous access to water and a 5% sucrose solution from
post-natal day 30 to 46. At adulthood (> 70 days), we investigated the impact of adolescent
diet on behavioral and neurobiological mechanisms associated with sweet reward processing.
We found that at adulthood, sucrose-exposed rats consumed less sweet rewards than control
water-exposed rats in a 2-bottle choice expressed less hedonic reactions to intra-oral infusion
of sweet solutions in a taste-reactivity protocol. These decreases in sweet preference and
hedonic reactivity to a sucrose challenge were associated with a lower c-Fos immunostaining
of the nucleus accumbens, especially in its anterior part. Interestingly, we also observed a
down regulation in the expression of both dopamine and opioid receptors in the nucleus
accumbens, involved respectively in the treatment of the motivational and hedonic properties
of food. These results demonstrate that adolescent sugar diet induces a decrease in the
motivational and hedonic perception of sweet food associated with a hypo-activation of the
nucleus accumbens playing a central role in these processes.
The neurobiological changes reported here could be linked to deficits in the processing of
hedonic and motivational properties of food rewards at adulthood, representing vulnerability
factors for the development of mood and feeding disorders.
(1) INCIA - UMR 5287 - CNRS - Univ Bordeaux - France
Naneix Fabien | [email protected]
FLAVONOIDS REVERSE SCOPOLAMINE-INDUCED LEARNING DEFICITS IN
NMRI MICE
Moreau, Pierre-Henri (1, 2) | Deiana, Serena (1, 2) | Melis, Valeria (1, 2) | Crouch, Barry (1)
| Harrington, Charles, R. (2, 3) | Wischick, Claude, M. (2, 3) | Riedel, Gernot (1)
Alzheimer’s disease (AD) is characterised by a progressive cognitive decline leading at the late
stage of the disease to dementia. The cholinergic system is widely recognised to be involved in
learning and memory and is affected in AD. Facilitation of cholinergic pathways became one of
the targets for the treatment of memory impairments leading to the development of cholinergic
enhancers which are currently the main therapy for AD. Natural substances such as flavonoids
have strong antioxidant capacity and are able to decrease brain acetylcholinesterase levels.
The aim of this study was to investigate a flavonoid, termed TRx1007, for its efficacy to reverse
spatial memory deficits induced by scopolamine and to establish its dose-response relationship.
We here assessed spatial cognition of female NMRI mice in a reference memory water maze
task. The animals received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by
vehicle, and/or TRx1007 (0.2 - 1 mg/kg) before the start of behavioural testing. Scopolamine
treated mice presented a considerable learning deficit in the water maze which was reversed
by TRx1007 at a dose of 1 mg/kg. This improvement of performance was confirmed with a
search strategy analysis showing a recovery with progressively more spatial swim patterns when
mice were exposed to 1 mg/kg TRx1007. No improvement was detected with a dose of 0.2
mg/kg.
In conclusion, administration of scopolamine in mice offers a suitable tool to mimic the
cholinergic deficit in AD and is widely used in pharmacological animal models for evaluation of
potential cognition-enhancing agents. In this model, we have shown that TRx1007 is able to
reverse the spatial learning deficits induced by scopolamine. These data provide compelling
evidence for TRx1007 as a novel memory enhancing drug for potential use in treating AD.
(1) School of Medical Sciences - University of Aberdeen - Aberdeen UK | (2) TauRx Therapeutics Ltd. Singapore | (2) Present address: Boehringer Ingelheim - Germany | (3) School of Medicine and
Dentistry - University of Aberdeen - Aberdeen UK
Moreau Pierre-Henri | [email protected]
IMPULSIVE AGGRESSION: THE INTERRELATIONSHIP BETWEEN TRAITS, SSRI
EFFICACY AND 5-HT1A RECEPTOR BINDING
Peeters, Deborah, G.A (1,2) | Van den Hurk, Koen (1) | Kogias, Nikos (1) | Verkes, RobbertJan (2) | Homberg, Judith, R. (1)
The impact of the serotonergic system in aggression has been extensively studied, but our
understanding remains inconclusive. Although low serotonin levels have been associated with
increased aggression and clinical studies show that selective serotonin reuptake inhibitors
(SSRIs) reduce aggressive behaviour, not all patients benefit from SSRI treatment. Since several
mood disorders are associated with the serotonergic system and aggressive patients scoring high
on neuroticism respond better to SSRIs, behavioural traits might be predictive for SSRI
responsivity. Furthermore, decreased 5HT1A receptor functionality in limbic regions is
associated with increased aggressive behaviour, and might play an important role in SSRI
responsivity.
In the present study we elucidated whether behavioural traits and 5HT1A receptor binding are
correlated with aggression and predict the anti-aggressive effect of SSRIs. An outbred strain of
Long Evans rats was tested in a resident-intruder paradigm to evaluate their aggressive
behaviour at baseline and after chronic SSRI treatment with escitalopram. Furthermore, several
tasks were used to evaluate behavioural traits, such as anxiety and impulsivity. Three weeks
after the final resident intruder interaction, in vivo 5HT1A receptor binding was measured using
[18F] MPPF PET scanning.
Based on percentage total offensive behaviour animals are divided into three aggression classes.
High aggressive animals tend to show signs of pathological aggression by attacking vulnerable
body parts and showing less warning signals. Furthermore, preliminary data already show that
high aggressive animals are less anxious on the elevated plus maze. Other data of the
behavioural tasks and treatment effects will be shown on the poster.
(1) Department of Cognitive Neuroscience - Donders Institute for Brain Cognition and Behaviour Nederland | (2) Department of Psychiatry - Radboud University Medical Centre - Nederland
Peeters Deborah G.A. | [email protected]
ADOLESCENT NICOTINE AND ALCOHOL EXPOSURE - EFFECTS ON
ENDOGENOUS OPIOID PEPTIDES IN RAT BRAIN
Granholm, Linnea (1) | Segerström, Lova (1) | Nylander, Ingrid (1)
Adolescence represents a period of extensive reorganization and maturation of brain circuitries
involved in emotions, motivation and cognition and, consequently, it is a period particular
sensitive to external stimuli such as drugs of abuse. The first drugs adolescents usually come in
contact with are alcohol and nicotine, either alone or in combination. This project aims to
investigate how two endogenous opioid peptides, dynorphin B and Met-enkephalin-Arg6/Phe7,
is affected after repeated exposures of nicotine and ethanol throughout adolescence. To model
adolescent episodic binge intake, outbred Wistar rats were subjected to either nicotine
(subcutaneously 1mg/kg) or ethanol (intragastric 2g/kg), alone or in combination. The animals
were treated for three consecutive days per week between postnatal day 28-59. Two hour after
the last exposure the animals were decapitated and their brains were dissected. The
immunoreactive levels of dynorphin B and Met-enkephalin-Arg6/Phe7 were analysed with
radioimmunoassay. In dorsal striatum, nicotine as well as the combination of nicotine and
ethanol increased the levels of Met-enkephalin-Arg6Phe7 whereas
ethanol alone had no effect. A combination effect of ethanol and nicotine as well as an effect
of ethanol alone were present in substantia nigra where the levels of Met-enkephalin-Arg6/Phe7
were decreased and in hypothalamus ethanol alone increased the levels of dynorphin B.
Endogenous opioids are implicated in alcohol and nicotine reward and addiction processes but
effects on the young brain remain elusive. The present results provide new evidence of longterm changes in opioid peptides as a consequence of adolescent ethanol and nicotine exposure.
(1) Department of Pharmaceutical Biosciences - Uppsala University - Sweden
Granholm Linnea | [email protected]
REGULATION OF MOTOR SYMPTOMS OF PARKINSON'S DISEASE BY
TARGETING SELECTIVE STRIATAL MUSCARINIC CHOLINERGIC RECEPTORS:
PHARMACOLOGICAL AND OPTOGENETIC APPROACHES
Ztaou, Samira (1) | Liberge, Martine (1) | Amalric, Marianne (1)
The striatal cholinergic (ACh) interneurons involvement in movement disorders has recently
received renewed interest. In Parkinson’s disease (PD) anticholinergic drugs were the first
widely accepted drugs before the discovery of L-DOPA. Their precise mechanism of action is
still not clear, although it is believed that they work by correcting the disequilibria between
striatal dopamine and acetylcholine activity in PD state. In this study, we examined the
involvement of striatal muscarinic cholinergic receptors in motor control in a lesional rodent
model of PD. We first confirmed that systemic administration of the nonselective muscarinic
receptor antagonist scopolamine reversed the motor symptoms (postural asymmetry and
turning bias) produced by unilateral nigrostriatal 6-OHDA lesions in mice. We then
demonstrated that the M1 and M4 muscarinic receptor subtypes were involved in these
beneficial effects by testing telenzepine and tropicamide (M1 and M4 receptor antagonist,
respectively) systemic administration in the same PD models. The involvement of a dorsal
striatal cholinergic overactivity in the expression of motor dysfunction in PD was tested after
local infusions of the M1 or M4 receptor antagonists and optogenetic manipulation of cholinergic
activity in transgenic mice specifically expressing halorhodopsin (eNpHR) in cholinergic neurons.
Photostimulation of eNpHR in the striatum of 6-OHDA lesioned mice inhibited ACh neuronal
activity and reduced the asymetric motor symptoms. This was reproduced by blocking either
M1 or M4 mACh receptors in the dorsal striatum. The present results indicate that cholinergic
modulation of the dorsal striatal circuit, particularly at M1 or M4 receptor subtypes, plays a
pivotal role in the regulation of the motor symptoms in PD.
This work is supported by ANR (ANR 2010-1416-02), France Parkinson, CNRS and AMU.
(1) Aix-Marseille University - CNRS UMR7291
Ztaou Samira | [email protected]
COMPARISON OF MOTOR ABILITIES IN INBRED AND OUTBRED MOUSE
STRAINS COMMONLY USED AS TRANSGENIC BACKGROUND
Riedel, Gernot (1) | Deiana, Serena (1) | Harrington, Charles, R (1,2) | Melis, Valeria (1)
Transgenic mice have become an invaluable tool for behavioural researchers interested in
modelling human neurodegenerative disorders. Several mouse lines have been created to mimic
hereditary forms of diseases and, in addition to their molecular and pathological
characterization, a comprehensive behavioural description is required to validate a mouse
transgenic model. Indeed, knowing the behavioural phenotypes is essential for molecular
geneticists to make the optimal choice of parental strains for the generation of mouse models
of human genetic diseases. For example, when modelling motor-related disorders, such as
Parkinson’s disease, one would avoid the use of a background mouse strain presenting with low
motor performance.
In the present study, we investigated the sensorimotor skills of 5 strains of mice which are
widely used in diverse research fields: three inbred (BALB/c, DBA/2 and C57BL/6J) and two
outbred (ICR and NMRI).
Sensorimotor abilities were assessed in 5-month old mice using a battery of motor tasks:
Hanging wire (to evaluate motor coordination and muscle strength), RotaRod (for motor
learning and motor coordination), Balance beam (for balance and motor coordination) and
CatWalk (for general locomotor activity and gait analysis).
Significant strain differences were detected in all behavioural tests employed. Inbred strains
displayed longer latency to fall in the hanging wire test when compared to outbred mice and
C57BL/6J within the former and NMRI for the latter group, presented with an overall superior
performance in the RotaRod test. In addition, NMRI were better than ICR in balance beam but
they needed more time than C57BL/6J to complete the task. Several differences were also
noticed in the CatWalk test suggesting strain-related difference in gait and locomotion.
These data showed that C57BL/6J within the inbred and NMRI for the outbred strains possessed
the best motor abilities, making them the most suitable background strains for models of motorrelated neurodegenerative diseases.
*Present address: Boehringer Ingelheim, Germany
(1) School of Medical Sciences - University of Aberdeen - UK | (2) School of Medine and Dentistry University of Aberdeen - UK | TauRx Therapeutics Ltd - Singapore
Riedel Gernot | [email protected]
THE NEUROTENSIN NTS1 RECEPTOR AGONIST PD149163 REDUCES FEARPOTENTIATED STARTLE IN MALE AND FEMALE MICE
Vanden Avond, Mark, A (1) | Smith, Claire (1) | Ritchie, Taylor (1) | Prus, Adam, J (1)
Neurotensin, a neuropeptide, has been associated with having anxiolytic effects, and systemic
administration of the NTS receptor agonist PD149163 has exhibited anxiolytic effects in male
rats. The present study sought to further evaluate the potential anxiolytic effects of PD149163
by assessing this compound in both male and female C57BL/J6 mice using the fear-potentiated
startle (FPS) paradigm. Startle chambers were equipped with a shock-grid floor, fluorescent
light, and an acoustic startle speaker. Conditioning took place between the light and floor
shock, and test sessions measured startle to a 120 dB noise burst while the light was on (FPS)
or off. Startle magnitude did not differ between the male and female mice. PD149163
produced significant reduction in FPS, with greater effects occurring in the female mice. The
anxiolytic and partial 5-HT agonist buspirone produced a significant reduction in FPS, which
was found to be greater in the male mice. The reduction in FPS by PD149163 coincides with
previous studies conducted in male rats. The greater reduction in FPS found in female mice
suggests that more research is needed to examine the neurotensin system and sex differences.
Overall, these findings support targeting the neurotensin system for the development of novel
strategies for treating anxiety disorders.
(1) Northern Michigan University - USA
Vanden Avond Mark A | [email protected]
THE VALUATION OF OUTCOME OF NEUROFEEDBACK TRAININGS
Wróbel, Andrzej (1) | Rogala, Jacek (1) | Paluch, Katarzyna (1) | Jurewicz, Katarzyna (1) |
Mikicin, Mirosław (2) | Krauz, Rafał (3) | Kublik, Ewa (1)
EEG-based neurofeedback (NFB) training aims to alter human behavior with help of continuous
feedback provided in a form of sensory information related to the trained EEG frequency band.
Healthy young participants were trained to up-regulate (n=6) and down-regulate (n=6) their
beta band (15-22 Hz) amplitude recorded from the scalp electrodes placed at frontal and
parietal positions (F3, F4, P3, P4) during visually guided computer-game. As a sham control we
used participants (n=7), whose feedback signal wasn’t related to recorded EEG but generated
by algorithm. Preliminary analysis showed that this NFB training was inefficient - we did not
observe any modification of the EEG beta band amplitudes neither within nor across the sessions
of EEG-NFB. Instead, in three participants from group trained to up-regulate beta, we observed
training-induced increase of beta-frequency activity, but of muscle origin. On average, EEGNFB trainings were perceived as having the true positive effect by trainers and trainees. Thus,
if the data were analyzed and presented according to the standards prevailing in the current
EEG-NFB literature, the result of the study could be presented as positive, i.e. up-regulation of
the beta band would be claimed successful on the basis of muscle artifacts or non-training
related effects.
Moreover, in all participants regardless of the training protocol, the power spectra of
spontaneous activity recorded during resting state with eyes open were significantly different
in frontal and occipital recordings before and after trainings. These differences were highest
in the beta range, intermediate in alpha (8-12 Hz), and non-significant in theta (4-9 Hz) and
gamma (30-45 Hz) bands. Such EEG changes may be attributed to nonspecific (e.g. attentional)
training effects which again do not allow confirming the effectiveness of the EEG-feedback
practice.
Supported by the Polish National Science Centre grant 2012/07/B/NZ7/04383.
(1) Nencki Institute of Experimental Biology - Warsaw - Poland | (2) University of Physical Education Warsaw - Poland | (3) Military University of Technology - Warsaw - Poland
Wróbel Andrzej | [email protected]
EFFECTS OF NEONATAL ALLOPREGNANOLONE MANIPULATIONS AND
EARLY MATERNAL SEPARATION ON ADULT VULNERABILITY TO DRUG
ABUSE: ETHANOL PREFERENCE AND DOPAMINE LEVELS IN VENTRAL
STRIATUM
Llidó, Anna (1) | Bartolomé, Iris (1) | Darbra, Sònia (1) | Pallarès, Marc (1)
Previous studies have shown that the neuroesteroid (NS) allopregnanolone (AlloP) could be
playing an important role during development, since changes in its neonatal levels lead to
alterations in adolescent and adult behaviors such as anxiety and novelty-directed locomotion,
traits related with vulnerability to initiate drug abuse. Early maternal separation (EMS) on
postnatal day (PND) 9 also causes behavioral and maturation alterations that could be related
to vulnerability to drug abuse. Additionally, some of the behavioral alterations caused by EMS
can be neutralized by the previous administration of AlloP. Thus, the aim of the present work
is to analyze if alterations in neonatal AlloP levels could lead to a higher vulnerability to alcohol
abuse in adult age, and if EMS could change these effects. We administered (s.c.) 10 mg/kg of
AlloP or 50 mg/kg of finasteride, a 5α reductase inhibitor, from PND5 to PND9, followed by 24h
of EMS at PND9. At PND70 we measured voluntary alcohol consumption using a two-bottle free
choice model, with one daily hour of access to the bottles (ethanol 10% (v/v) + glucose 3% (w/v)
vs. glucose 3% (w/v)) during two weeks. After this procedure, ventral striatum samples were
obtained to determine monoamine levels. Results revealed that neonatal finasteride
administration causes an increase in both ethanol and glucose consumption in adulthood. EMS
decreases ethanol preference during the first days of procedure, and previous AlloP neutralizes
this effect. Both finasteride and AlloP animals that did not suffer EMS had lower levels of DA
and 5-HT in ventral striatum, with their corresponding turnover ratios increased. Taken
together, these results reveal that both neonatal alterations could alter vulnerability to alcohol
abuse and corroborate that adequate neonatal NS levels are crucial for a correct CNS
development, showing a relationship between EMS and neonatal AlloP levels.
This work was supported by grants from the Spanish Ministry of Economy and
Competitiveness (PSI2012-36646).
(1) Institut de Neurociències - Universitat Autònoma de Barcelona - Spain
Llidó Anna | [email protected]
IDENTIFYING INDVIDUAL DIFFERENCES IN DRUG VULNERABILITY USING A
T-TEST METHOD
Rice, Beth Ann (1) | Akins, Chana, K (1) | Keller, Peggy, S. (2)
The attribution of incentive salience to cues that become associated with drugs of abuse is a
critical characteristic of individuals who may be vulnerable to drug addiction. In preclinical
models, individual differences in the attribution of incentive salience is determined by
examining the propensity to sign or goal track. Researchers typically screen for sign and goal
trackers using an autoshaping procedure. Animals with the propensity to sign track more than
others are thought to be more vulnerable to drug abuse and relapse. Typically, a one-third
rank order split is used to classify sign trackers (STs) and goal trackers (GTs). This relative
criterion is prone to misclassification, which is problematic because these classifications are
used to test drug-related phenomena. The current study illustrates a method of classifying STs
and GTs using a single-sample t test in which a subject who spends significantly more time sign
tracking than goal tracking across trials is classified as ST, and the opposite is classified as GT.
In the current experiment, male quail received a light followed by visual access to a female
quail for 125 trials. A single-sample t test was used to determine whether each subject spent
significantly more time near the light (STs) or more time near the female (GTs), and this was
compared to classification based on a traditional third-split. Two subjects that on average
engaged in more goal tracking than sign tracking, but not significantly so, were classified as
intermediates using the t test but were misclassified as STs using the third split. Three subjects
who engaged in significantly more goal tracking than sign tracking were classified as GTs by the
t test but as intermediates using the third split. Thus, results indicate more accurate
classification of STs and GTs using the t test compared to using the traditional third split.
(1) Department of Experimental Psychology - University of Kentucky - United States | (2) Department
of Psychology - University of Kentucky - United States
Rice Beth Ann | [email protected]
ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTORS AGONIST REVERSE
COGNITIVE AND SENSORIMOTOR GATING DEFICITS IN A SCHIZOPHRENIALIKE MODEL IN RATS
Potasiewicz, Agnieszka (1) | Nikiforuk, Agnieszka (1) | Kos, Tomasz (1) | Piotr, Popik (1)
Alpha 7 nicotinic acetylcholine receptors (α7 nAChRs) are involved in the regulation of cognitive
processes. Furthermore, it has been suggested that α7 nAChRs might be implicated in the
pathophysiology of schizophrenia. Hence, selective activation of α7 nAChRs is considered to be
a potential therapeutic strategy aimed at ameliorating cognitive dysfunctions associated with
schizophrenia. Preclinical data indicated that orthosteric ligands, like the partial α7 nAChR
agonist, A582941, produced procognitive effects, but little is known about efficacy of this
compound in animal models of schizophrenia.
The aim of present study was to evaluate the efficacy of A582941 against MK-801-induced
schizophrenia-like deficits in rats. Prepulse inhibition of startle response test (PPI), discrete
paired-trial delayed alternation task in a T-maze and five-choice serial reaction time task (5CSRTT) were employed in this study.
A582941 reversed the sensorimotor gating and working memory impairment evoked by MK-801
as assessed in the PPI test and T-maze, respectively. However, this compound did not affect
the rats’ attentional performance in the 5-CSRTT.
The present study demonstrates the beneficial effects of α7 nAChRs agonist on sensorimotor
gating and some aspects of cognition in rats tested in impaired conditions. Therefore, our
results support the notion that α7 nAChRs may constitute a useful targets for procognitive
therapy in schizophrenia.
Acknowledgements: This study was supported by the Polish National Science Centre grant NCN
2012/07/B/NZ/01150 and statutory funds from the Institute of Pharmacology, Polish Academy
of Sciences (Krakow, Poland). Agnieszka Potasiewicz is a holder of scholarship from the KNOW
sponsored by Ministry of Science and Higher Education, Republic of Poland.
(1) Institute of Pharmacology-Polish Academy of Sciences-Poland
Potasiewicz Agnieszka | [email protected]
DIFFERENTIAL INVOLVEMENT IN AMYGDALA NUCLEI IN THE ACQUISITION
AND MAINTENANCE OF HABITUAL COCAINE-SEEKING BEHAVIOUR
Murray, Jennifer, E (1) | Fouyssac, Maxime (2) | Everitt, Barry, J (1) | Belin, David (2)
The transition from goal-directed to habitual drug seeking has been shown to rely on a
functional shift in dominance of dopamine control of drug seeking behavior from the ventral to
the dorsolateral striatum (DLS) with dorsal striatal dopamine maintaining high rates of drug
seeking driven by contingent presentations of a drug-associated conditioned stimulus (CS). We
have tested the hypothesis that the amygdala, which is not directly connected with the DLS,
mediates the impact of Pavlovian drug-associated stimuli on the functional, intrastriatal shifts
underlying cocaine seeking habits. We have previously demonstrated that the basolateral
amygdala (BLA) and central nucleus of the amygdala (CeN) mediate the expression of cocaineseeking habits. These results arose from the use of functional disconnections whereby pretraining unilateral BLA or CeN lesions were combined with dopamine receptor blockade in the
contralateral DLS, but did not differentiate the relative contribution of these domains of the
amygdala to the acquisition or maintenance of cocaine-seeking habits. The present experiments
investigated the effects of amygdala-dorsal striatal disconnections involving both pre- and posttraining inactivations of the BLA or CeN combined with contralateral DLS dopamine receptor
blockade. The results show that BLA activity is required for the acquisition, rather than
maintenance, of DLS dopamine control of habitual drug-seeking behavior. By contrast,
functional connectivity between the CeN and the DLS is required for the maintenance of
habitual cocaine seeking. These results demonstrate that the shift to DLS control over cocaineseeking behaviour that is elicited by drug-associated CSs requires both the BLA and the CeN,
but that the relative dominance of the control exerted by the amygdala itself undergoes a
transition from BLA to CeN between the acquisition and the maintenance of well-established
performance of the cocaine CS-dependent habit.
(1) Department of Psychology - University of Cambridge UK | (2) Department of Pharmacology University of Cambridge UK
Murray Jennifer E | [email protected]
SEROTONIN-DOPAMINE INTERACTIONS BETWEEN THE ORBITOFRONTAL
CORTEX AND AMYGDALA IN MARMOSETS
Jackson, Stacey, AW (1,2) | Horst, Nicole, K (1,2) | Robbins, Trevor, W (1,2) | Roberts,
Angela, C (2,3)
Orbitofrontal (OFC) serotonin has been shown to be crucial for normal performance in reversal
learning, a paradigm widely used to investigate cognitive flexibility. However, the OFC is just
one component of a circuit important for reversal learning; other previously identified
structures include the striatum and amygdala to which the OFC sends strong projections. Given
that the OFC can modulate activity in the serotoninergic and dopaminergic neurons of the dorsal
raphé and ventral tegmental area respectively and thus has the potential to affect levels of
these monoamines subcortically, we determined the effects of OFC serotonin depletion on
monoamine activity in the striatum and amygdala. Following unilateral selective serotonin
depletion of the anterior OFC with 5,7 dihydroxytryptamine in five marmoset monkeys, we
performed localised dissections within the ipsi- and contralateral striatum and amygdala and
measured post-mortem tissue monoamine levels using high performance liquid chromatography
(HLPC). A robust, significant up-regulation of dopamine was observed in the ipsilateral
amygdala but no changes were seen in the ipsilateral striatum and no other changes in
monoamine function were observed in either the striatum or amygdala. Possible implications
of this work for the understanding of reversal learning and cognitive flexibility, and its wider
relevance for understanding compulsivity, as in e.g. obsessive-compulsive disorder (OCD), will
be discussed.
This study was funded by a Wellcome Trust Senior Investigator Award 104631 /Z/14/Z (to TWR)
and conducted within the University of Cambridge Behavioural and Clinical Neuroscience
Institute, supported by a joint award from the MRC and the Wellcome Trust. SAWJ was
supported by a BCNI-MRC Studentship.
(1) Department of Psychology - University of Cambridge UK | (2) Behavioural and Clinical
Neuroscience Institute - University of Cambridge UK | (3) Department of Physiology - University of
Cambridge UK
Jackson Stacey AW | [email protected]
ALCOHOL-SEEKING BEHAVIOR IS ATTENUATED BY INHIBITING µ-OPIOID
RECEPTORS: EVIDENCE FROM TWO NOVEL ANIMAL MODELS
Giuliano, Chiara (1) | Peña-Oliver, Yolanda (1) | Bullmore, Edward, T (2) | Goodlett,
Charles, R (3) | Belin, David (4) | Everitt, Barry, J (1)
One of the most challenging aims in pre-clinical research is to develop animal models that can
provide valuable, reliable and translational tools with which to investigate specific aspects of
neuropsychiatric disorders relevant to pharmacotherapeutics. Two characteristic features of
addiction are that drug-seeking behaviour is elicited by drug-associated environmental stimuli
and is compulsive, being maintained despite aversive or negative consequences. Here we
introduced two novel and complementary animal models enabling the investigation of: i)
alcohol-associated stimuli-maintained seeking behaviour and ii) compulsive alcohol seeking
behaviour. In the first model, alcohol-preferring (P) rats were trained to respond instrumentally
for alcohol under a second-order schedule of reinforcement, in which a prolonged period of
alcohol-seeking behaviour was maintained by contingent presentation of an alcohol-associated
conditioned reinforcer followed by 20-min free-access to alcohol. In the second model, we
further adapted a seeking-taking chained schedule of alcohol intake in which instrumental
seeking responses in P rats resulted either in the opportunity to drink alcohol, or in
unpredictable mild foot-shock punishment. In a subgroup of animals, alcohol-seeking persisted
despite the unpredictable, intermittent delivery of 0.45 mA foot-shock punishment. That same
subgroup of animals also showed increased alcohol-seeking behaviour under extinction
conditions and increased motivation for alcohol measured under a progressive-ratio schedule
for alcohol. Seeking behaviour under both tasks was also challenged by systemic treatment with
the novel selective µ-opioid receptor antagonist GSK1521498, which reduced both compulsive
and non-compulsive alcohol-seeking behaviours, as well as alcohol drinking. Taken together
with our earlier work showing that GSK1521498 also prevented cue-maintained cocaine- and
heroin-seeking, these data indicate the great potential for selective µ-opioid receptor
antagonism in relapse prevention and abstinence promotion across addictive drug classes.
(1) Department of Psychology - University of Cambridge UK | | (2) Department of Psychiatry University of Cambridge UK | (3) Department of Psychology - Indiana University Purdue University
Indianapolis - USA | (4) Department of Pharmacology - University of Cambridge UK
Giuliano Chiara | [email protected]
Quantity discrimination by zebrafish (Danio rerio)
Potrich, Davide (1) | Sovrano, Valeria Anna (1,3) | Stancher, Gionata (2) | Vallortigara
Giorgio (1,3)
Discrimination of numerical quantity was investigated in zebrafish (Danio rerio). Male zebrafish
chose to approach the location previously occupied by the larger in number between two groups
of female conspecifics (no longer visible at test) in sets of 1 versus 2 and 2 versus 3 items but
failed at 3 versus 4 items; similarly, when tested with larger numbers zebrafish succeeded with
2 versus 4, 4 versus 6 and 4 versus 8 items but failed with 6 vs 8 items. The results suggest that
zebrafish rely on an approximate number system to discriminate memorized sets of conspecifics
of different numerousness, the degree of precision in recall being mainly dependent on the
ratio between the sets to be discriminated.
(1) Center for Mind/Brain Sciences - University of Trento - Italy | (3) Department of Psychology and
Cognitive Sciences - University of Trento - Italy | (2) Fondazione Museo Civico di Rovereto - Italy
[email protected]
Potrich Davide | [email protected]
THE EFFECTS OF AN ACUTE PSYCHOSOCIAL STRESSOR AND DRUG CUE
EXPOSURE ON CRAVING AND STRESS REACTIVITY IN CANNABIS USERS
Round, Jason, T. (1) | Harrison, Amanda, A. (2) | Shepherd, Therese, E. (1) | Kolokotroni,
Zoe, K. (1)
Drug addiction is characterised by increased reactivity to stress and drug-related cues and loss
of control over drug use. Previous work in cocaine users indicates that exposure to stressors
and drug-related cues may increase subjective drug craving and stress in a comparable manner.
The current study was designed to assess the effects of acute psychosocial stress and drug cue
exposure on subjective drug craving and stress in regular cannabis users.
Utilising a within subject design, 34 cannabis users were exposed to a psychosocial stressor or
drug-related cues over two test sessions. The Trier Social Stress Test (TSST) was conducted as
a psychosocial stressor and the drug-related cues comprised of a video depicting cannabis
preparation and manipulation of cannabis-related paraphernalia. Measures of cannabis craving
(Marijuana Craving Questionnaire-Short Form; MCQ) and measures of stress (State Trait Anxiety
Inventory-State and stress measured on a VAS scale) were taken before and after each
treatment.
In cannabis users, stress increased significantly after exposure to the TSST, but not drug-related
cues. However, craving, as measured by the expectancy and purposefulness subscales of the
MCQ, reflecting intention to use and anticipation of positive drug effects, increased
significantly after both the TSST and drug-related cues. Although non-significant, craving as
measured by the compulsivity subscale followed a similar pattern to expectancy and
purposefulness. Interestingly, the emotionality measure of craving, reflecting anticipated druginduced relief from negative affect, only significantly increased after the TSST not the drugrelated cues.
In conclusion drug-related cues and stressors differentially affect the subjective experiences of
drug craving and stress in cannabis users. Unlike cocaine users, cannabis users are more
sensitive to the effects of stressors than drug cues. Findings suggest cannabis dependent
individuals may require distinct treatment strategies to those abusing psychostimulants, which
acknowledge the potentially greater impact of stressors relative to drug-related cues in relapse.
(1) Leeds Beckett University UK | (2) University of Leeds UK
[email protected]
Leeds Beckett University - United Kingdom | [email protected]
BREAKING A DRUG SEEKING HABIT TRIGGERS ABERRANT COCAINE
SEEKING BEHAVIOUR AT RELAPSE
Pena-Oliver, Yolanda (1) | Giuliano, Chiara (1) | Puaud, Mickael (2) | Belin, David (2) |
Everitt, Barry, J (1)
Cocaine addiction is considered to stem from the development of maladaptive drug seeking
habits that contribute to the maintenance of drug use despite aversive consequences, and to
high rates of relapse. However, the relative contribution of habits and pharmacological
withdrawal from the drug to relapse is unknown. In this study we demonstrate that preventing
rats from expressing their drug seeking habits after forced abstinence results in aberrant,
compulsive drug seeking behaviour at relapse. Thus, rats were trained under a fixed-interval
(FI) 15-min schedule or a FI 15 (FR10:S) second order schedule of reinforcement, the latter
having been shown to recruit stimulus bound, dorsolateral striatum-dependent, maladaptive
habits. Indeed, in this procedure every ten active lever presses produces the presentation of
a 1s (CS) so that rats respond more vigorously for the drug in the presence of the CS. The results
showed that a 3-day forced abstinence period increased cocaine seeking responses only in the
group trained under second-order schedule of reinforcement, while cocaine abstinence had no
effect in the FI 15 group who responded for cocaine but without earned drug cue presentations.
In order to test if this increase in responding depended on the motivational effect of
pharmacological withdrawal from cocaine, rats then received non contingent cocaine injections
while being prevented from responding for the drug for a 3-day “instrumental seeking
abstinence” period. The results showed that despite receiving the same amount of cocaine as
during the self-administration sessions, only the rats with a history of CS-dependent cocaine
seeking habits displayed the robust increase in cocaine seeking after abstinence. These results
strongly suggests that the expression maladaptive seeking habits, rather than pharmacological
drug withdrawal itself, contribute to addiction by invigorating drug seeking behaviour in
individuals under abstinence, indicating a core psychological component of the addiction cycle.
(1) University of Cambridge - Department of Psychology UK | (2) University of Cambridge Department of Pharmacology UK
Pena-Oliver Yolanda | [email protected]
HYDROXYPROPYL BETA CYCLODEXTRIN (HPΒCD) FACILITATES THE
REVERSAL OF SCOPOLAMINE-INDUCED COGNITIVE IMPAIRMENT BY
DONEPEZIL IN THE RAT FEAR CONDITIONING TEST
Van Craenendonck, Hansfried (1) | Ver Donck, Luc (1)
Scopolamine potently blocks muscarinic receptors resulting in pronounced, yet reversible
behavioral changes in rodents. Efforts over the last 50 years have led to a comprehensive
characterization of scopolamine’s effects on cognitive performance in rodents, but surprisingly
there is still debate as to whether the impairments are specifically learning and memory
related: previous studies have demonstrated that scopolamine’s non-specific side effects may
confound association between a conditional stimulus (CS=context) and an aversive
unconditional stimulus (US=foot shock) when administered before acquisition. However,
administration following acquisition failed to disrupt memory consolidation.
We have demonstrated that an HPβCD-scopolamine conjugate can be used in the fear
conditioning test to disrupt memory consolidation in the absence of scopolamine’s confounding
side-effects.
In this study we evaluated whether HPβCD, as a vehicle for scopolamine, could facilitate the
effect of donepezil on the scopolamine disruption compared to the effect on scopolamine
dissolved in saline.
Male Long Evans rats were co-treated with donepezil (1 mg/kg; sc) and scopolamine either
dissolved in 3% HPβCD or saline (0.16 mg/kg; sc) 30 minutes prior to acquisition (one foot shock;
0.7mA, 1sec). 24h later, animals were placed back in the test chambers and freezing behavior
was recorded (recall).
Scopolamine, dissolved in saline, significantly reduced duration of freezing in both the
acquisition and recall trials. Although, when dissolved in HPβCD, scopolamine did not disrupt
freezing during the acquisition phase, while a significant decrease was observed during recall.
During recall, donepezil had no significant effect on the disruptive effect of scopolamine in
saline group but significantly reversed the disruption of the memory consolidation produced by
the HPβCD-scopolamine conjugate.
This study demonstrates that scopolamine in HPβCD causes memory impairment in the absence
of behavioral side effects and that donepezil has a stronger effect on the HPβCD-scopolamine
conjugate than on the scopolamine in saline solution.
(1) Dept Neuroscience-Janssen Research and Development-Belgium
Van Craenendonck Hansfried | [email protected]
INCREASING LEVELS OF THE ENDOGENOUS CANNABINOID ANANDAMIDE IN
THE BASOLATERAL AMYGDALA IMPAIRS RETRIEVAL OF PAVLOVIAN FEAR
MEMORIES IN RATS
Ratano, Patrizia (1) | Carlucci, Maurizia (1) | Campolongo, Patrizia (1)
The endocannabinoid system is a crucial modulator of memory processing. Cannabinoid
receptors are highly expressed in cortico-limbic regions, such as the hippocampus, basolateral
complex of the amygdala (BLA) and prefrontal cortex, where they predominately modulate both
excitatory and inhibitory signaling within specific neuronal circuits involved in learning and
memory processes for emotionally arousing experiences. Although evidence regarding
cannabinoid effects on memory retrieval is limited, the majority of studies show that exogenous
cannabinoid agonists induce detrimental effects on memory retrieval.
Here we investigated the effects induced by pharmacological manipulation of the
endocannabinoid signaling in the hippocampus or in the BLA on retrieval of traumatic events.
To this aim, adult male Sprague Dawley rats were trained in an Auditory Fear Conditioning task
(AFC), and bilaterally infused into the dorsal hippocampus or the BLA, 60 minutes before the
retrieval, with the Fatty Acid Amide Hydrolyse (FAAH) inhibitor, URB597, or the
Monoacylglycerol lipase (MAGL) inhibitor, KML29, in order to increase endogenous levels of the
endocannabinoids anandamide (AEA) or 2-arachinoyglycerol (2-AG), respectively.
We found that exogenous manipulation of the hippocampal endocannabinoid signaling does not
affect memory retrieval in the AFC. Interestingly, intra-BLA administration of URB597 induced
an impairing effect on memory retrieval of conditioned fear trough activation of CB1 receptors.
No effects were found after intra-BLA administration of KML29.
Our findings provide the first evidence that the endocannabinoid anandamide is a key player in
memory retrieval in the AFC task, thus paving the way to new potential therapeutic intervention
for the treatment of neuropsychiatric disorders where a previous exposure to traumatic events
could alter the response to trauma reminder leading to mental illness
(1) Sapienza University of Rome - Italy
Ratano Patrizia | [email protected]
INHIBITORY CONTROL, IMPULSIVITY AND USE OF DRUGS IN TEENAGERS
FROM SOUTH OF BRAZIL
De Almeida, Rosa Maria (1) | Willhelm, Alice (1) | Joao Centurion Cabral (1)
Adolescence is characterized by the maturation of emotional and cognitive skills that provide
capabilities for independent functioning during adulthood. The last region to develop in the
central nervous system is the prefrontal cortex, linking the ability to control impulses. As
illustrated by the consumption of licit and illicit drugs that is increasingly prevalent in the lives
of adolescents. The overall objective was to evaluate the impulsivity, the inhibitory control
and use of drugs in pre-teens and teens between the age of 10 and 16. The specific objectives
were to compare impulsivity and inhibitory control among boys and girls, from three age groups
and between students from public and private schools. The sample consisted of 190 individuals
(from 10 to 12, n=52, 13 and 14 years, n= 49 and 15 to 16, n=89) of public and private schools
from Porto Alegre (Brazil). The instruments used were: Strengths and Difficulties Questionnaire,
Questionnaire on the onset of drug use, Barrat impulsiveness scale-youth, Go/No-go task, Five
Digits test and Wechsler Abbreviated Scale of Intelligence (WASI). Statistically significant
differences were observed (p <=0.01) in performance between the three age groups, showing a
chronological increase in inhibitory control. In some subtests of the Five Digits Test, students
in private schools had better performance. Approximately 60% of adolescents have tried alcohol
and 17% illegal drugs. Pre-teens are consuming alcohol increasingly earlier and in greater
quantities. We can conclude that inhibitory control capacity increases throughout adolescence.
In addition, public school students showed worse performance in inhibitory control and greater
impulsivity, and these data suggest that the environment in which the adolescents live is related
to the performance deficits. Girls showed less inhibitory control than boys, making more errors
of omission in the Go/No-go task, suggesting that in this sample, girls have higher attentional
impulsivity than boys.
(1) Universidade Federal do Rio Grande do Sul - Brasil
De Almeida Rosa M.M. | [email protected]
COGNITIVE TRANSLATION: HOW COULD IT BE BETTER?
(1) Gyertyán, István
While basic research keeps on identifying newer and newer cognitive enhancer mechanisms,
clinical development of these drugs faced 100% attrition rate in the last decade. The factors
underlying this considerable translational gap are manifold, but 1) inappropriate selection of
molecular targets, 2) low translational value of animal models, and 3) improperly composed
patient populations are regularly brought into focus. Novel approaches are required in all the
three areas and a combination of them will likely be necessary to radically improve translational
efficacy.
Molecular targets coming out from basic research need rigorous validation in relevant animal
models to check their suitability for industrial drug development projects. Our insufficient
knowledge on disease pathomechanisms render symptomatic treatment a more feasible
approach than the theoretically ideal disease 'modifying' one. Animal tests used so far detected
a large number of false positive (clinically ineffective) compounds demonstrating their
inappropriateness for target validation. Impairing elementary memory functions (passive
avoidance, novel object recognition) by a single dose of e.g. scopolamine, may well not be a
valid model of the profound cognitive deficits characterising the human disease. More complex
paradigms with better face validity (e.g. attentional set-shifting) should be used and coupled
to multiple types of cognitive impairment - to compensate for the above mentioned knowledge
gap. A 'cognitive domains x impairing methods' matrix of tests will provide better prediction for
clinical efficacy than the actually fashioned simple 'gold standard' assay.
Cognitive deficits of neurological and psychiatric disorders show diverse patterns; this patternspecificity may require compounds with different mode of actions. 'Fitting' the clinical target
population to the properties of the drug candidate (stratification of the patients by symptomgroups or along genetic, biochemical variables) and/or restricting the application of the drug
to certain phases of the disease or as adjunct to cognitive therapy may further increase the
success rate.
(1) MTA-SE NAP B Behavioural Pharmacology Group - Hungary
Gyertyán István | [email protected]
CHEMOGENETIC EXCITATION OF DORSOMEDIAL PREFRONTAL CORTEX
PRINCIPAL NEURONS ON THE OVEREXPECTATION OF FEAR
Yau, Joanna, O. Y (1) | McNally, Gavan, P (1)
Pavlovian fear conditioning is governed by prediction error, the discrepancy between actual
and unexpected outcomes. In this way, prediction error is positive when an outcome is
unexpected and negative when an outcome is less than expected, subsequently driving
increments and decrements in learning respectively. One demonstration of negative prediction
error is overexpectation. In overexpectation, rats are presented with tone-shock and lightshock pairings in Stage I. Then in Stage II, rats in the overexpectation group are presented with
tone+light-shock pairings whilst a Control group was not given this training. At test, the
overexpectation group shows lower fear responses towards each cue presented separately
compared to the Control group due to negative prediction error during Stage II - the expected
shock from both the tone and light exceed the shock that occurred and results in the loss of
fear. Whilst chemogenetic excitation of rat dorsomedial prefrontal cortex (dmPFC) principal
neurons restores prediction error during expected CS-US pairings to drive learning when it does
not normally occurs (Yau & McNally, 2015), the dmPFC influence on negative prediction errors
is unknown. Here we used a chemogenetic approach to investigate whether dmPFC principal
neuron excitation can counteract negative fear prediction to prevent the loss of fear learning
during overexpectation. Rats with dmPFC principal neurons transfected with the hM3Dq DREADD
or eYFP were subjected to an overexpectation paradigm. Clozapine-N-oxide was injected prior
to Stage II training. Results on dmPFC excitation on the overexpectation of fear will be reported.
(1) UNSW - Australia
Yau Joanna O. Y. | [email protected]
CHEMOGENETIC EXCITATION OF BLA GLUTAMATERGIC NEURONS
MODULATES FEAR PREDICTION ERRORS
Sengupta, Auntora (1) | Bagley, Elena, E (29 | McNally, Gavan, P (1)
We used chemogenetics to investigate the causal role of BLA glutamatergic neurons in
instruction of fear learning by prediction error. Rats received applications of AAV5-CamKIIhM3Dq or AAV5-CamKII-eYFP to BLA. CNO caused membrane depolarisation and increases in
action potential firing rate in vitro and robust neuronal activation in vivo. We then used
behavioural procedures to investigate fear prediction error. To isolate positive prediction error
we utilised a blocking procedure. Rats were trained fear conditioned stimulus (CS) A in Stage
I. In Stage II, rats received pairings of CSA compounded with an auditory CSB and shock. Blocking
was shown by less fear to CSB at test than a control group that did not receive Stage I training.
CNO (3 mg/kg, i.p.) prior to Stage II prevented blocking and enabled normal fear learning in
CamKII-hM3Dq rats. This prevention of blocking was not due to an increase in arousal, attention,
memory consolidation or asymptotic levels of learning because hM3Dq activation had no effect
on acquisition of fear learning across different shock US intensities. To isolate negative
prediction error, we utilised an overexpectation procedure. Rats were trained fear CSA and
CSB in Stage I via pairings with shock. In Stage II rats were given CSAB pairings with shock.
Overexpectation was shown by less fear to CSA and CSB than a control group that did not receive
Stage II training. CNO (3 mg/kg, i.p.) prior to Stage II prevented overexpectation in CamKIIhM3Dq but not CamKII-eYFP rats. These experiments show that activity of BLA glutamatergic
neurons is causal to predictive fear learning. Manipulations that increase their activity mimic
positive prediction error signal to disrupt the associative blocking of fear without simply
augmenting US processing. Further, these increases disrupt a negative prediction error signal
to attenuate over expectation - a finding consistent with the direct (i.e. Rescorla-Wagner) and
not indirect (Pearce-Hall) coding of prediction error on fear learning.
(1) UNSW - Australia | (2) University of Sydney - Australia
Sengupta Auntora | [email protected]
ROSTRAL AND CAUDAL HIPPOCAMPAL LESIONS DIFFERENTLY AFFECTED
ON EXPLORATORY ACTIVITY AND RISK ASSESSMENT OF MICE IN TUNNEL
TEST
Kuptsov, Pavel A. (1) | Lebedev, Ilya V (1) | Manyukhina, Victoria O (1) | Deacon, Robert M. J
(1) | Pleskacheva, Marina G. (1)
Numerous data suggest that the hippocampus is involved in exploratory behaviour. Studies of
selective lesions, however, are rare. The tunnel test consisted of a narrow alley (38.0×5.5cm).
From each side of each end, a 40mm diameter black plastic tube was bent in a C-curve back to
the other end of the alley. There was a transparent front along one long («open») side of the
central alley and opaque wall along other («closed») side. It is known that complete
hippocampal lesions reduce time in the tubes and the number of visits into tubes (Deacon &
Rawlins, 2005).
We studied the effects of caudal or rostral bilateral cytotoxic (NMDA) lesions (about 1/3 of the
whole hippocampus for both lesions) on behaviour in the tunnel-test in male C57BL/6 mice.
Mice were placed in the centre of the alley and videotaped for 5 min. We used Observer
software (Noldus) for detailed offline analysis of behaviour of fast-moving mice.
Control mice spent 45% total time in the tubes. In contrast to whole hippocampal lesion, a
number of entries in tubes was increased in both rostral and caudal groups. However analogous
to total lesions trend to decrease total time spent in tubes was found in selective lesion groups.
Moreover mean duration of visit to tube was decreased in mice with selective lesions. These
impairments were higher in rostral group.
In spite of similarity of both tubes, control animals avoided the tube which goes to the “open
side”. They spent less time here and latency of first entry was higher in “open side” tube than
in “close side”. Selective lesions groups did not demonstrate side preference.
The findings revealed that rostral lesion more impaired exploratory behaviour than caudal
lesion. However any selective hippocampal lesions probably eliminate processes of risk
assessment on distant extra-maze information. Supported by RFBR13-04-00747
(1) Faculty of Biology Lomonosov Moscow State University
Kuptsov Pavel A. | [email protected]
HYPO-FRONTAL ACTIVITY IN THE PATIENTS WITH PONTINE INFARCTS
DURING WORD RETRIEVAL: A NEAR-INFRARED SPECTROSCOPY STUDY
Obayashi, Shigeru (1) | Hara, Yukihiro (1)
Cognitive impairments after stroke might interfere with return to work of the patients. The
damage to the subcortical structures as well as the cortical ones can cause the deficits, partly
because of the cerebro-cerebellar diaschisis. The phenomenon may involve the frontocerebellar-thalamic loop via the brainstem, each of which might play a different role for the
information processing throughout the loop, but the detail remains unsolved. Now, to test
whether the pontine ictus could affect any frontal activity, we used the 22-channel nearinfrared spectroscopy system (ETG-4000 Optical Topography System; Hitachi Medical Co., Tokyo,
Japan) to measure hemodynamic response changes in the frontal cortex of the patients with
the pontine ischemia (mean age 64.5 years: ranged 48-74) during verbal fluency task (VFT). The
3 x 5 probes were attached to each subject’s superior frontal area, whose long axis was
arranged orthogonally to the line connecting inion to nasion. The probes were symmetrically
positioned centering on Fz, in accordance with the international10/20 system for EEG electrode
placement. For cognitive assessment, MMSE (mini-mental-state-test), Trail making test, WAISPIQ as well as VFT performance during NIRS measure were conducted. These neuropsychological
results suggested their inattention and word retrieval difficulties while the intelligences
seemed intact. SPECT indicated that most of the patients showed no abnormal perfusion around
the frontal cortex. However, NIRS study suggested that the patients showed less frontal
response during VFT than age-matched healthy subjects. Thus, the damage to the pons can
produce hypo-frontal activity during VFT, thus resulting in the inattention and word retrieval
difficulty. The findings may support the interaction between the frontal cortex and the
brainstem.
(1) Department of Rehabilitation Medicine - Chiba Hokusoh Hospital Nippon Medical School-Japan
Obayashi Shigeru | [email protected]
DIFFERENTIAL EFFECTS OF D2/3 RECEPTOR AVAILABILITY AND DRUG
EXPOSURE IN HIGH AND LOW IMPULSIVE RATS
Barlow, Rebecca, L (1) | Wearn, Alfie (1) | Gorodetskaya, Natalia (1) | Stiller, Detlef (1) |
Nicholson, Janet, R (1) | Pekcec, Anton (1)
Impulsivity is a multi-faceted behavioural construct which can broadly be defined as a tendency
to act prematurely and without foresight. It is symptomatic of several neuropsychiatric
disorders including schizophrenia, ADHD and substance abuse disorders, and can be observed
behaviourally as impaired response inhibition (motor impulsivity) or the preferential choice of
risky or immediate rewards (choice impulsivity). Maladaptive impulsivity may arise due to
dysfunctional interactions between the prefrontal cortex and ventral striatum. Previous work
has shown that rats expressing high levels of motor impulsivity have reduced dopamine D2/3
receptor availability in the ventral striatum, as compared to low impulsive rats. In this study,
we investigated whether high levels of choice impulsivity were also associated with decreased
D2/3 receptor availability, using [18F]fallypride PET imaging. Additionally, we assessed
whether drugs which directly or indirectly affect dopaminergic neurotransmission within frontostriatal circuitry have dissociable effects on impulsivity in rats selected for high and low
impulsive behaviour on the five-choice serial reaction time task (5CSRTT); namely cocaine,
amphetamine, MK801 and yohimbine. A negative correlation was observed between impulsive
choice and [18F]fallypride binding potential in the ventral striatum of high but not low impulsive
rats. These results indicate that low D2/3 receptor availability in the ventral striatum may
influence both choice and motor impulsivity as a consequence of altered dopaminergic tone;
which could possibly explain the dissociable effects of dopaminergic manipulations in high and
low impulsive rats.
(1) Boehringer Ingelheim - Germany
Barlow Rebecca L | [email protected]
PUPILLARY AND OCULOMOTOR MARKERS OF TRAIT ANXIETY BIASES ON
ATTENTIONAL NETWORKS: INSIGHTS FROM SEX DIFFERENCES APPROACH
Ciobanu, Teofil (1) | Ruggeri, Paolo (1) | Lew, Eileen (2) | Brandner, Catherine (1)
Anxiety is associated with disruptions of the frontal-amygdala circuitry that induce biases in
normal processing of sensory information. In particular, anxiety can increase attention towards
potentially threatening stimuli, but also entrains broader attentional changes regardless of
threat. Cortical origin of controlled attention is thought to be supported by activations of
fronto-parietal and temporal neural networks. These mechanisms have been correlated with
several oculometric parameters, including autonomic pupillary responses, when the control of
attention is manipulated. Finally, state and trait anxiety measured by means of self-report
questionnaires often indicate higher anxiety level in women by comparison with men. Because
attentional tasks performance can be disrupted in a differential manner by anxiety, this study
aims at assessing whether pupillary responses can be used as an online measure of allocation
and fluctuations in attention in male and female non-clinical participants. High (N = 45) and
low (N = 59) female and male anxious participants were tested in the ANT-I task (Callejas et
al., 2004) where attentional spread was manipulated by varying visual and auditory cueing with
congruent or incongruent flankers. Continuous measurement of pupil diameter and saccadic
movements were recorded with a fixed-head eye-tracking system during the whole task.
Preliminary results indicate that: I) oculometric parameters can reflect processing of sensory
information; II) anxiety level might disrupt pattern of pupil diameter variations as well as
oculomotor behaviour depending of the attentional demand of the task; III) gender differences
were present only in high anxiety group when invalid cues and incongruent flankers were
present. Taken together, these data suggest that the interaction of sex and anxiety is able to
disrupt attentional processes regardless of threat. They suggest as well that the pupil diameter
might be involved in the control of attentional spread during cognitive processes.
(1) Laboratory of Experimental Research on Behavior - Institute of Psychology - University of Lausanne
- Switzerland | (2) Faculty of Engineering - Computing and Science - Swinburne University of
Technology - Malaysia
[email protected]
Ciobanu Teofil | [email protected]
EXTENSIVE AND RIGOROUS TRAINING IN CANINE LEADS TO HIGH
STANDARD OF ACCURACY IN FORENSIC HUMAN ODOR IDENTIFICATION
PERFORMANCES
Marchal, Sophie (1) | Bregeras, Olivier (1) | Puaux, Didier (1) | Gervais, Remi (2) | Ferry,
Barbara (2)
Odorology is a forensic method based on a comparison between an olfactory sample collected
from an object that has been in contact with a human individual and that of a suspect. Based
on the greater olfactory ability of dogs to detect and process odors, this method has been used
in forensic investigations to identify the odor of a suspect at a crime scene. The excellence in
reliability and repeatability of the method largely depends on the rigor in the dog’s training.
The present study is the first one to describe with great precision the different steps of the
training that lead to highest levels of dog’s performances in olfactory detection and
discrimination. The main results of our study show that olfactory detection specificity level
rapidly reaches 100% efficiency after the beginning of continuous training, while the level of
olfactory detection sensitivity significantly improved throughout continuous training, reaching
90% efficiency when the complexity of the odor presented in the sample was similar to that
presented in the lineup. This highest level in olfactory detection accuracy ensures reliable
results obtained during official human scent identification line-ups. Importantly, our data
should convince the law enforcement authorities to use human identifications results as official
forensic evidence when dogs are trained appropriately.
(1) Division of the Technical and Scientific Police - Forensic Section - Odorology Group - 31 Avenue
Franklin Roosevelt F-69134 Ecully Cedex France | (2) Centre of Research in Neuroscience Lyon - UMR
CNRS 5292 - INSERM U 1028 - Université Claude France
Ferry Barbara | [email protected]
ALLOCENTRIC SPATIAL LEARNING AND MEMORY DEFICITS IN DOWN
SYNDROME
Banta Lavenex, Pamela, A (1) | Bostelmann, Mathilde (2) | Brandner, Catherine (1) |
Costanzo, Floriana (3) | Fragnière, Emilie (1) | Klencklen, Giuliana (1) | Lavenex, Pierre (1) |
Menghini, Deny (3) | Vicari, Stefano (3)
Studies have shown that persons with Down Syndrome (DS) exhibit impaired visuoperceptual
memory, whereas their visuospatial memory capacities appear comparatively spared. However,
most of the evidence concerning preserved visuospatial memory comes from tabletop or
computerized experiments which are biased towards testing egocentric (viewpoint-dependent)
spatial representations. Accordingly, allocentric (viewpoint-independent) spatial learning and
memory capacities may not be necessary to perform these tasks. Thus, in order to more fully
characterize the spatial capacities of individuals with DS, allocentric processes underlying realworld navigation must also be investigated. We tested 20 participants with DS and 16 mental
age-matched, typically developing (TD) children in a real-world, allocentric spatial memory
task. We found that although there was significant individual variation, as a group participants
with DS performed worse than TD children on all measures of task performance, suggesting
persistent and pervasive deficits in hippocampus-dependent memory in DS.
(1) Laboratory for Experimental Research on Behavior-Institute of Psychology-University of Lausanne
Switzerland | (2) University of Geneva Switzerland | (3) Department of Neuroscience-Bambino Gesù
Children’s Hospital-Rome Italy
Banta Lavenex Pamela | [email protected]
CONTROL OF VISUO-SPATIAL ATTENTION IN COMPLEX ENVIRONMENTS:
BEHAVIOUR, FUNCTIONAL IMAGING AND BRAIN-LESION DATA
Nardo, Davide (1) | Console, Paola (1) | Reverberi, Carlo (2) | Paolucci, Stefano (1) |
Doricchi, Fabrizio (1,3) | Macaluso, Emiliano (1)
Mechanisms of attention control have been extensively studied using behavioural,
neuropsychological and imaging methods. However, the vast majority of the previous studies
employed simple and artificial stimuli. We present a study that used rich and dynamic visual
material (video-clips) to investigate attention control in a more realistic setup. We combined eyemovements, computational models of visuo-spatial attention (saliency), functional imaging and
lesion mapping in neglect patients to investigate mechanisms of spatial orienting.
In healthy participants we found that visual saliency predicted fixation patterns, but only when the
videos included competing events on both sides of space. Functional imaging showed activation
of the dorsal and the (right) ventral fronto-parietal networks during free-viewing of the videos, with
a further increase of activity in ventral regions when the videos included events on both sides. In
neglect patients with lesions in the right ventral network, we found a fixation-bias toward the right
side specifically when the videos included events on both sides and a reduction of the correlation
between saliency and fixations.
We propose that the right ventral network detects events in the environment and, together with
the dorsal network, governs orienting towards the location of relevant events. When multiple
events are present, additional information is required to identify relevant locations and the dorsal
system utilizes saliency to guide orienting. Lesions of the ventral system impair events detection,
but also affect saliency-driven control in the intact dorsal system.
We conclude that naturalistic situations with multiple events and a high level of competition require
the ventral attention network to detect relevant events, as well as dorsal areas that can use
stimulus saliency to control orienting. Our results support models of visuo-spatial attention that
emphasize the interaction between the dorsal and the ventral fronto-parietal attention control
networks.
(1) Fondazione Santa Lucia - Rome - Italy | (2) Università di Milano Bicocca - Psychology Department Milan - Italy | (3) Università La Sapienza - Psychology Department - Rome - Italy
Macaluso Emiliano | [email protected]
DOES OPTIMISM MAKE YOU A GAMBLER? - FIRST RESULTS FROM ANIMAL
MODEL
Rafa, Dominik (1) | Kręgiel, Jakub (1) | Nikiforuk, Agnieszka | Kubik, Jakub | Popik, Piotr |
Ryguła, Rafał
Although pathological gambling is a serious social problem in modern societies, information
about behavioral traits that could determine vulnerability to this pathology is still meager. In
this study, using a recently developed ambiguous-cue interpretation (ACI) paradigm we took
the unique opportunity to investigate whether “optimism” as a trait may determine the
gambling-like behavior in rodents. In a series of ACI tests (cognitive bias screening), we
identified rats displaying “pessimistic” and “optimistic” traits. Subsequently, using the rat slot
machine task paradigm, we investigated if the optimistic/pessimistic traits could shape the
crucial aspect of gambling-like behaviors investigated in rats and humans: interpretation of the
“near-miss” outcomes as a win or as a loss situation.
We found that “optimistic” rats did not interpret “near-miss” as a win trials more often than
their “pessimistic” conspecifics. Optimists however were more likely to act optimistically in
hopeless situations such as total or near loss.
The results are discussed in terms of interrelation between different behavioral traits and
gambling.
Supported by the National Science Centre (Research grant: OPUS 7 2014/13/B/NZ4/00214 to
RR) and the statutory funds of the Institute of Pharmacology Polish Academy of Sciences.
Supported by the grant NR 72/H/E/13 from the Ministry of Health programme: “Support for
scientific research into gambling and other non-substance addictions along with problem
solving”, co-financed from the Gambling Problem Solving Fund.
Dominik Rafa is a holder of scholarship from the Know sponsored by Ministry of Science and
Higher Education, Republic of Poland.
(1) Polish Academy of Sciences - Poland
Email: [email protected] | [email protected] | [email protected] | [email protected] | [email protected] | [email protected]
Rafa Dominik | [email protected]
NEUROANATOMICAL BACKGROUND OF PESSIMISM: THE ROLE OF
PREFRONTAL AND ORBITOFRONTAL CORTICES IN COGNITIVE JUDGMENT
BIAS IN RATS
Kregiel, Jakub, JK (1) | Rafal, Rygula (1) | Joanna, Golebiowska (1)
Cognitive judgmen bias (optimism/pessimism) has been associated with many affective
disorders including depression and anxiety. It is therefore surprising that its neuroanatomical
background remains still largely uninvestigated. In the present study, using recently developed
ambiguous-cue interpretation (ACI) paradigm we assumed the challenge to investigate the
effects of excitotoxic lesions of chosen brain regions on cognitive judgment bias in rats.For this
the previously trained animals were subjected to bilateral excitotoxic lesions of the prefrontal
(PFC) and orbitofrontal (OFC) cortices and were subsequently tested using ACI paradigm.The
rats subjected to the OFC lesions were significantly more pessimistic than their SHAM or PFC
operated conspecifics. The results of our study clearly show involvement of the OFC but not
PFC in mediation of cognitive judgment bias in animals. These findings are discussed along with
the results of neuroimaging studies in humans.
This work was supported by the National Science Centre (Research grant: Sonata bis dec2012/07/E/NZ4/00196 to RR) and the statutory funds of the Institute of Pharmacology Polish
Academy of Sciences.
(1) Institute of Pharmacology - Polish Academy of Sciences - Poland
KregielJakubJK | [email protected]
PROBABILISTIC SCHEDULES OF REWARD FOR ASSESSING THE ROLE OF 5HT2C RECEPTORS IN COGNITIVE FLEXIBILITY
Borton, Maxine L. (1) | Clifton, Peter G. (1)
Deficits in flexible cognition are associated with many neuropsychiatric conditions, yet remain
a challenge for existing treatments. Therefore animal models used to develop novel procognitive drugs must have high translational value. Probabilistic reversal learning (PRL) tasks,
which assess ability to reverse learned associations on the basis of both accurate and misleading
information, may allow more direct comparison to human paradigms than conventional tasks
that offer only accurate response feedback. In addition, they provide measures of reward and
punishment prediction accuracy and sensitivity through analysis of choice behaviour in response
to spurious feedback, which are of theoretical and clinical relevance. Although implemented
successfully in non-human primates and rats, it has been suggested that mice are challenged
by some aspects of these tasks. In order to further validate use of probabilistic tasks in mice
and also examine the role of 5-HT 2C receptors in flexible cognition, this study examined the
effect of the 5-HT 2C receptor antagonist SB242084 (0.5mg/kg) on PRL task performance in
C57BL/6J mice. Probability of inaccurate feedback was set at a threshold of p = .02 (2/10
correct responses punished, 2/10 incorrect responses rewarded) and the location of the correct
response was reversed over three serial tests. The majority of animals demonstrated successful
reversal learning, and both groups showed accurate reward prediction at both the correct and
incorrect location by late-stage reversal. Importantly the animals responded appropriately in
trials providing both accurate and misleading feedback. SB242084-treated mice showed
improved performance on the first reversal test, requiring fewer sessions and incorrect trials
to criterion compared with controls. The present study validates the use of PRL tasks in mouse
models, and identifies a more ecologically valid and sensitive tool for assessing the effects of
serotonergic manipulations on flexible responding. Research funded by a BBSRC (UK) Doctoral
Studentship.
(1) School of Psychology - University of Sussex - United Kingdom
Borton Maxine L | [email protected]
ACTIVATION OF MOTION AREA V5 IS SUFFICIENT FOR DISCRIMINATION OF
THE ORIENTATION OF MOVING STIMULI BUT NOT FOR THEIR CONSCIOUS
PERCEPTION
Pedersini, Caterina, A. (1) | Zoccatelli, Giada (2) | Lingnau, Angelika (3) | Moro, Sancho (1) |
Sanchez-Lopez, Javier (1) | Bollini, Alice (1) | Savazzi, Silvia (1) | Marzi, Carlo, A. (1)
Hemianopia is a visual field defect characterized by decreased vision or blindness in the
contralateral visual field of both eyes due to a lesion along the post-chiasmatic visual pathway.
Despite loss of vision, some unconscious visual abilities (“blindsight”) could be present in the
blind field. The probability of finding this phenomenon can be increased by showing moving
stimuli in the blind field. Therefore, the aim of this project was to assess the role of area V5 in
yielding conscious or unconscious perception of moving visual stimuli. We assessed fMRI
activation of V5 using full field moving random dots in a patient with hemianopia. We used a
3T scanner in a session including Retinotopic Mapping, V5 Localizer and DTI (performed to
compare the integrity of white matter fibers, eg. optic radiation). We found that this patient
showed activation of extrastriate visual areas including V5 despite no activation of V1.
Interestingly, he performed above chance albeit unconsciously only in an orientation
discrimination task with moving but not static stimuli. In conclusion, this preliminary result in
a single case provides evidence that in the absence of V1 the presence of V5 activation is
necessary for above-chance performance with moving stimuli but is not sufficient for perceptual
awareness. This has relevance for understanding the neural bases of perceptual awareness.
Funded by ERC-2013-ADG “Perceptual Awareness”
(1) Department Neurological and Movement Sciences - University of Verona - Italy | (2) Department of
Neuroradiology - University Hospital - Verona - Italy | (3) Center of Mind/Brain Sciences - University
of Trento - Mattarello - Italy
[email protected] | [email protected] | carloalberto.marzi@uni
Pedersini Caterina A. | [email protected]
NEONATAL ALLOPREGNANOLONE MANIPULATION AFFECTS SENSITIVITY
TO STIMULATING EFFECTS OF ALCOHOL IN ADULTHOOD: POSSIBLE ROLE
IN DRUG ABUSE VULNERABILITY
Bartolomé, Iris (1) | Llidó, Anna (1) | Darbra, Sònia (1) | Pallarès, Marc (1)
Neonatal levels of the neurosteroid allopregnanolone are crucial for brain development and
adult behavior. An increase of neonatal allopregnanolone levels induces anxiolytic-like effects
and improves exploration in novel environments in adulthood, behavior that can be related to
a sensation seeking pattern, which has been described to be related to drug abuse vulnerability.
In the present experiment we have studied the effects of neonatal allopregnanolone levels
alteration on the sensitivity to the alcohol stimulant effects in adulthood. For this purpose, we
have injected allopregnanolone or finasteride, an allopregnanolone synthesis inhibitor, from
postnatal day 5 to 9. In adolescence (30 days old), half of the subjects were injected with
progesterone, the main allopregnanolone precursor, as changes in adolescent levels could also
alter adult behavior. In adulthood (70 days old), locomotor activity induced by the stimulating
effects of alcohol was evaluated in a computerized open field. The results indicate that low
doses of ethanol (0,5g/kg) produced stimulating effects in open field test, increasing locomotor
activity, and this effect was not present in the animals that were neonatally treated with
finasteride, showing lower locomotor activity scores. Moreover, progesterone administration in
adolescence decreased locomotor activity also in the subjects neonatally injected with
allopregnanolone or vehicle. There were no differences in locomotor activity between neonatal
or adolescent treatments in response to injections of high alcohol dose (0,8g/kg). Finally, in
the animals that did not received alcohol (adult vehicle group), neonatal vehicle injection
increased locomotor activity in comparison with no handled animals. Also, neonatal
allopregnanolone or finasteride decreased this injection effect. In conclusion, the manipulation
of neurosteroids levels in crucial stages of development (neonatal and/or adolescent ages) plays
an important role in the effects of alcohol on locomotor activity, suggesting a possible role on
the vulnerability to develop drug abuse.
This work was supported by a grant from the Spanish Ministry of Economy and Competitiveness
(PSI2012-36646).
(1) Institut de Neurociències - Universitat Autònoma de Barcelona - Spain
[email protected]
Bartolomé Iris | [email protected]
HISTONE DEACETYLASE 5 LOSS-OF-FUNCTION MUTATION MODERATES
THE EFFECTS OF THE EXPOSURE TO EARLY LIFE STRESS ON COCAINE
SEEKING BEHAVIOR
Valzania, Alessandro (1) | Viscomi, Maria Teresa (1) | Carola, Valeria (1)
Considerable emphasis of neuroscience research is directed toward the identification of genetic
variations that predispose to drug addiction. Increasing evidence suggests that these gene
expression changes are mediated in part by epigenetic mechanisms that alter chromatin
structure. In preclinical models, it has been shown that chronic cocaine induces changes in
histone acetylation, a mechanism which serves to relax the chromatin structure and permits
greater access to transcriptional activators. Histone acetylation is typically catalysed by
enzymes with histone acetyltransferase or histone deacetylase (HDAC) activity. Among the
different HDAC genes, the HDAC5 is of particular interest due to its high expression in key
regions of the brain reward circuitry. Recent studies have highlighted a role for the HDAC5 gene
in the modulation of the cocaine reward process. In parallel the same enzyme has been
described as modulator of the response to chronic stress. Here, we aimed to investigate
whether genetic variation in mouse HDAC5 gene moderates the effect of the exposure to a
stressful early environment on cocaine seeking behavior. We exposed wild type and HDAC5
mutant (heterozygous; Het) mice to chronic stress (social isolation, SI) in early age (postnatal
week 3) and tested their cocaine-seeking behavior by conditioned place preference test in
adulthood. Interestingly, Het mice developed high level of cocaine seeking behavior only when
they had been exposed to SI in early age. Additionally, these mice were not able to extinguish
cocaine-seeking behavior despite a long time of withdrawal. In order to identify the
neurobiological substrates mediating this phenotype, we assessed the brain activation induced
by cocaine in these mice by c-FOS immunohistochemistry. This analysis pointed out the
hippocampus and nucleus accumbens as key structures differentially activated by cocaine in
Het mice experiencing SI in early age.
(1) IRCSS Fondazione Santa Lucia - Italy
valzania alessandro | [email protected]
AFFECTIVE ULTRASONIC COMMUNICATION: SEROTONIN TRANSPORTER
RATS SHOW ENHANCED BEHAVIORAL RESPONSES TO AMPHETAMINE DUE
TO REDUCED 5-HT2C RECEPTOR FUNCTIONING
Kisko, T, M.(1) | Oetzel, K.(1) | Willadsen, M.(1) | Vörckel, K, J.(1) | Seffer, D.(1) |
Schwarting, RKW.(1) | Homberg, J.(2) | Wöhr, M.(1)
Rats emit 50-kHz ultrasonic vocalizations (USV) in response to drugs of abuse, such as
amphetamine (AMPH). It is widely believed that they reflect a positive affective state, possibly
associated with drug wanting and/or liking. We recently found that the neurotransmitter
serotonin (5-HT) is involved in the modulation of appetitive 50-kHz USV in response to AMPH,
as 50-kHz USV emission was blocked by administration of the 5-HT2C receptor agonist CP
809,101, while being enhanced by the 5-HT2C receptor antagonist SB 242084 (Wöhr et al.,
Psychopharmacology, 2015). Here, we show that rats lacking the serotonin transporter (SERT)
emit more appetitive 50-kHz USV in response to AMPH than heterozygous and wildtype
littermate controls. AMPH-induced hyperactivity did not differ between genotypes. Moreover,
deficits in pre-pulse inhibition following AMPH administration were seen irrespective of
genotype. Thus, the effects of AMPH on sensorimotor functions appear not to be affected by
the lack of SERT. This indicates that SERT is specifically involved in modulating the rewarding
aspects of AMPH, with AMPH being more rewarding in SERT knockout rats. Importantly, the
increase in appetitive 50-kHz USV in SERT knockout rats is likely due to long-term changes in
the 5-HT system. In fact, we found that appetitive 50-kHz USV emission following AMPH was
not enhanced in wildtype controls when the selective 5-HT reuptake inhibitor escitalopram was
co-administered. To identify relevant long-term changes in the 5-HT system, we targeted the
5-HT2C receptor and found that AMPH-induced behavioral alterations were not inhibited by the
agonist CP 809,101 in SERT knockout rats, while a clear inhibition was seen in heterozygous and
wildtype littermate controls. In support of the specificity of the involvement of the 5-HT2C
receptor, we further showed that the behavioral alterations induced by AMPH were potentiated
by the antagonist SB 242084 in controls but not in SERT knockout rats.
(1) Philipps Universität - Marburg - Germany | (2) Radboud University - Nijmegen -The Netherlands
Kisko Theresa. M | [email protected]
NICOTINE INDUCED IMPULSIVE CHOICE IS MEDIATED BY BOTH THE Α4Β2
AND Α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN RATS
Kolokotroni, Katerina, Z (1) | Harrison, Amanda, A (2)
Consistent with theories that propose a critical role for impulsive behaviour in drug addiction,
heavy smokers exhibit greater levels of impulsive choice than non-smokers and research has
suggested that this may in part be a consequence of the direct effects of nicotine. Whilst
nicotine has been shown to increase impulsive choice in rats, the precise receptor mechanisms
mediating this effect remain unknown. A series of studies were designed to examine the role
of α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) in nicotine induced impulsive choice
in rats.
Male Lister Hooded rats (N=15) were trained on a systematic delayed reward task until choice
behaviour was both stable and sensitive to delay. Rats were presented with a choice between
two levers, one of which delivered a single food pellet, and the other which delivered a larger
reward of 5 food pellets after a delay of 0, 10, 20 40 or 60 seconds. Following training, doseresponse functions for the α4β2 nicotinic acetylcholine receptor antagonist dihydro-βerythroidine (DHβE; 0, 1, 3, 6mg/kg sc) and the α7 nicotinic acetylcholine receptor antagonist
methyllycaconitine (MLA; 0, 5, 10mg/kg ip) were established in separate groups of rats. The
ability of selected doses of DHβE and MLA to antagonise the effects of acute nicotine (0.5mg/kg
sc) was then explored.
When administered alone DHβE and MLA did not alter performance in the delay discounting
task. Acute administration of DHβE however, dose-dependently blocked nicotine induced
impulsive choice, whilst pre-treatment with MLA blocked the effects of nicotine at the 5mg/kg
dose. The present findings support a role for both the α4β2 and α7 receptor subtypes in
mediating the effects of nicotine on impulsive choice and suggest that these receptors may be
potential therapeutic targets for nicotine addiction.
(1) Faculty of Health and Social Sciences - Leeds Beckett University UK | (2) Institute of Psychological
Sciences - University of Leeds UK
Kolokotroni Katerina Z | [email protected]
EVOLUTION OF THE BRAIN’ MORPHOLOGICAL CHARACTERS OF
LABROIDES DIMIDIATUS AND CLOSELY RELATED SPECIES FROM FAMILY
LABRIDAE
Chojnacka, Dominika, I (1) | Barski, Jaroslaw, J (1)
It is currently widely accepted that the complexity of a species’ social life is a major
determinant of its brain complexity, as predicted by the social brain hypothesis. However, it
remains a challenge to grasp what social complexity exactly is and what the best corresponding
measures of brain anatomy are. The apparent complexity of cleaner fish behavior makes them
a prime candidate to evaluate the potential link between complex social behavior and the
complexity of brain structures. Cleaners recognize clients individually, they remember past
interactions with clients, they may cooperate, cheat, manipulate, reconcile, produce signals
out of context, and use predatory clients as social tools against aggressive clients (Bshary 2006).
Using my own data concerning cytoarchitectonic study of the brain of the obligatory cleaner
Labroides dimidiatus, facultative cleaner Thalassoma lunare and closely related species that do
not clean at all I investigated whether the cytoarchitectonic of the brain of Labroides provides
any indication that their Machiavellian behaviour is associated with a more complex brain
structure. Here I present the evolution of morphological characters of the brain that was
mapped using reliable phylogenetic relationships (Westneat and Alfaro, 2005) in MacClade4.08
software based on the Fitch’s parsimony.
Synapomorphies of individual clades and
autosynapomorphies for individual studied species were identified. My results show that
centers located in the telencephalon involved in skills associated with complex social behavior,
differ qualitatively and quantitatively between cleaners and species with less complicated
behavior.
(1) Center for Experimental Medicine in Katowice - Medical University of Silesia - Katowice - Poland
Chojnacka Dominika I | [email protected]
DISSOCIATING
‘WANTING’
AND
ANTICIPATED
‘LIKING’
FROM
CONSUMMATORY ‘LIKING’ IN SMOKERS WITH DIFFERENT LEVELS OF
NICOTINE DEPENDENCY
Selby, Danielle L (1) | Harrison, Amanda A (2) | Shepherd, Therese E (1) | Kolokotroni, Katerina Z (1)
The Incentive Sensitisation theory (Robinson and Berridge, 1993) suggests ‘wanting’ and ‘liking’
are dissociable concepts, with ‘wanting’, but not ‘liking’ typically increasing with repeated drug
use. ‘Wanting‘ is associated with anticipation of reward (before drug intake), whereas ‘liking’
relates to perceived pleasure derived from consummatory behaviour (during/after drug use).
However, numerous studies attempting to parse these components of reward have
misconceptualised ‘liking’ as an anticipatory cognition, assessing how much participants think
they would like the reward, prior to consumption. This study explores whether levels of nicotine
dependency differentially effect ‘wanting’ and ‘liking’ responses to smoking-related cues, and
whether anticipated and consummatory ‘liking’ are equivalent, and dissociable from ‘wanting’.
Heavy (HS, mean=16 cigarettes/day) and light non-daily (LS, mean=2 cigarettes/day) smokers
completed ‘wanting’ and anticipated ‘liking’ questionnaires pre- and immediately post-exposure
to smoking-related and neutral cues, and 45 minutes later (end of session). Consummatory ‘liking’
was measured post-session, whilst smoking.
‘Wanting’ and anticipated ‘liking’ responses revealed identical patterns of results in HS and LS.
At baseline, no differences were seen between HS and LS on ‘wanting’ or anticipated ‘liking’,
however immediately after exposure to both cues, and at the end of sessions, HS reported greater
drug ‘wanting’ and anticipated ‘liking’ than LS. Irrespective of smoking group, smoking-related
cues increased ‘wanting’ and anticipated ‘liking’ compared to neutral cues and this effect was
maintained until end of session. Conversely, HS and LS did not differ on consummatory ‘liking’.
Analyses confirmed the relationship between ‘wanting’ and anticipated ‘liking’ was significantly
stronger than ‘wanting‘ and consummatory ‘liking’ or anticipated and consummatory ‘liking’.
‘Wanting’ and anticipated ‘liking’ appear to be equivalent concepts measuring anticipation of
reward, both of which are dissociable from consummatory ‘liking’. Furthermore, heavier smoking
increases anticipatory desire for rewards, but not smoking pleasure. Future research attempting
to dissociate these concepts should ensure ‘liking’ is appropriately measured after consumption.
(1) Psychology Department - Leeds Beckett University UK | (2) Institute of Psychological Sciences University of Leeds UK
[email protected]
Selby Danielle L | [email protected]
THE RELATIONSHIP BETWEEN THE GENOTYPE OF NEURONAL NITRIC
OXIDE SYNTHASE AND SENSORIMOTOR GATING IN HUMANS
Rovný, Rastislav (1) | Roháriková, Veronika (1) | Murínová, Jana (1) | Cimrová, Barbora (1) |
Bendžala, Štefan (1) | Repiská, Gabriela (2) | Minárik, Gabriel (2) | Katina, Stanislav (1,3) |
Riečanský, Igor (1,4)
Evidence is growing that a gaseous neurotransmitter nitric oxide (NO) plays a role in the
pathogenesis of schizophrenia. Several studies have reported an association between
schizophrenia and the genetic variability of neuronal nitric oxide synthase (nNOS), the enzyme
responsible for nitric oxide production in neurons. Prepulse inhibition of the acoustic startle
reflex (PPI), a measure of sensorimotor gating efficiency, is an important endophenotype and
translational biomarker of schizophrenia. We investigated the relationship between PPI and the
genetic variability of nNOS in healthy adult humans. We found that PPI was significantly weaker
in carriers of nNOS risk alleles. These data provide support for the possible role of nitric oxide
in schizophrenia. This work was supported by Ministry of Health of the Slovak Republic under
the project registration number 2012/52-SAV-2, and VEGA (projects no. 2/0080/13, 2/0093/14,
and 2/0165/15).
(1) Inst. of Normal and Pathological Physiology - Slovak Academy of Sciences - Bratislava - SK | (2) Inst.
of Molecular BioMedicine - Comenius Univ. Bratislava - SK | (3) Masaryk Univ. - Brno - CZ | (4) Social,
Cognitive and Affective Neuroscience Unit - Department of Basic Psychological Research and Research
Methods - Faculty of Psychology - Univ. of Vienna - AT
Rovný Rastislav | [email protected]
POSTSYNAPTIC 5-HT1A RECEPTORS AND REGULATION OF BODY
TEMPERATURE IN MICE
Feja, Malte (1) | Noto, Bettina (1) | Fink, Heidrun (1) | Dietze, Silke (1)
Thermoregulation is a vital function in both humans and animals with the serotonin (5-HT)
system, in particular the 5-HT receptor, playing a major role. Activating 5-HT receptors by the
5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) leads to reduced
body temperature. While there is consensus that hypothermia is induced by the stimulation of
postsynaptic 5-HT1A receptors in rats and humans, the regulatory mechanisms in mice are less
clear. In our group, within phenotyping a transgenic mouse line permanently overexpressing
the 5-HT1A receptor in serotonergic projection areas, Bert et al. (2008, PMID: 18396339)
revealed exaggerated 8-OH-DPAT-provoked hypothermic response.
Thus, in the present study, we used radio telemetry as a non-invasive technique to monitor the
basal body temperature and the hypothermic effect of different doses of 8-OH-DPAT (0.1 mg/kg
- 4 mg/kg i. p.) in male transgenic mice in comparison to NMRI wild-type males. 5-HT1A
overexpressing mice revealed lower levels of basal body temperature than wild types
(transgenic mice: 36.0 °C; NMRI wild-type mice: 37.4 °C). In both genotypes, systemic
administration of 8-OH-DPAT dose-dependently decreased body temperature, being
significantly more pronounced in mutant mice (-2.8 °C compared to -1.5 °C in NMRI wild types).
Dose response curves of 8-OH-DPAT revealed an ED50 = 0.4 mg/kg in transgenic and an ED50 =
0.57 mg/kg in NMRI wild-type mice, pointing towards an involvement of the postsynaptic 5HT1A receptor in the regulation of body temperature in mice.
Additionally, we investigated whether reduction of serotonergic activity by pretreatment with
the 5‑HT synthesis inhibitor parachlorophenylalanine (PCPA) would alter the effects of 8-OHDPAT on body temperature in transgenic mice postsynaptically overexpressing the 5‑HT1A
receptor. The fact that 8-OH-DPAT-evoked thermal responses were not influenced by
pretreatment with PCPA further substantiates a contribution of postsynaptic 5-HT1A receptors
to thermoregulation in mice.
(1) Institute of Pharmacology and Toxicology - School of Veterinary Medicine - Freie Universität Berlin
- Germany
[email protected]
Feja Malte | [email protected]
PERCEPTUAL BIAS IN THE RIGHT PARIETAL CORTEX , A TMS-EEG STUDY
Molteni, Federica (1) | Parisi, Giorgia (2) | Mazzi, Chiara (1) | Salatino, Adriana (3) | Ricci,
Raffaella (3) | Savazzi, Silvia (1)
The right posterior parietal cortex (rPPC) is involved in visuo-spatial processing, as neglect
patients and TMS studies revealed. Two different research tools have contributed to acquire
this knowledge: first, the Landmark task, that affords to disentangle between perceptual and
response biases and second, the hunting procedure, a new TMS protocol to identify the parietal
spot that best modulates visuo-spatial perception.
By combining EEG and TMS, we want to observe the change induced in the brain activity after
the stimulation. The experiment followed the subsequent steps: screening and baseline
assessment of perceptual bias; hunting procedure delivering ten single pulses for each of the 9
points of a grid centrally located over P6, while the subject is performing a line bisection
judgments task, namely the Landmark task; administration of Landmark task while recording
EEG with and without the stimulation of the parietal hotspot. Two types of stimuli were used
for the Landmark task: symmetrically and asymmetrically bisected lines. Participants were
divided in two different groups depending on the presence (n=8) or the absence (n=7) of a
perceptual bias in the Landmark task.
Results have shown a difference in the P2N2 complex between the two groups, independently
of the type of the stimulus. In particular, this peak-to-peak amplitude was reliably larger for
the group showing perceptual bias (p<=.05). Furthermore a late positive (LP) component,
peaking at the same latencies both with and without TMS, was produced by asymmetrically
bisected lines (p<=.001), while it was absent for the symmetrically ones. Moreover, TMS had
the effect of enhance the amplitude of both components (P2N2: p<=.05; LP: p<=.001).
The present results thus show that the rPPC is involved in magnitude estimation of line length
and that the effect of TMS in inducing a perceptual bias relates to the early stages of the
perceptual processing of the stimuli.
(1) Department of Neurological and Movement Sciences - University of Verona - Italy | (2) Department
of Psychology and Cognitive Science - University of Trento - Italy | (3) Department of Psychology University of Turin - Italy
Molteni Federica | [email protected]
IMMUNOHISTOCHEMICAL ANALYSIS OF ADULT NEUROGENESIS IN MICE
WITH AN OVEREXPRESSION OF THE POSTSYNAPTIC 5-HT1A RECEPTOR
Sander, Svenja, E (1) | Noto, Bettina (1) | Klempin, Friederike (2) | Alenina, Natalia (2) |
Bader, Michael (2) | Fink, Heidrun (1)
With a 6-month prevalence of 17% in Europe, depression represents a common mental disorder
with an enormous social and economic impact. Recent studies shed light on a possible
involvement of altered serotonin1A receptor (5-HT1AR) -mediated adult neurogenesis and
gliogenesis in the pathophysiology of depression. However, the exact underlying mechanisms
remain unclear, mainly due to the diverse external and internal influences on neurogenesis and
the complexity of the serotonergic system with its various receptors and their locations. Mice
with permanent overexpression of postsynaptic 5-HT1ARs (OE mice) represent a unique tool for
investigating the involvement of postsynaptic 5-HT1ARs in this context. Previous studies
demonstrated correct 5-HT1A receptor coupling and functioning in OE mice. Here, we examined
proliferation and survival of newborn cells in the adult dentate gyrus (DG) of OE mice in
comparison to wild-type (WT) mice. Ten weeks old OE and WT mice were treated with
bromodeoxyuridine (BrdU) to label newly generated cells. (50 mg/kg intraperitoneally on three
consecutive days). Animals were killed either one day (proliferation) or 21 days (survival) after
the last injection. For labelling of newborn cells, immunohistochemistry for BrdU (1:500)
followed by the peroxidase method was performed. Proliferation as well as survival in the adult
DG of new born cells in the dentate gyrus of OE mice was significantly increased. According to
previously observed sex differences, a further analysis revealed only significant increases in the
number of newly generated cells in the female but not in the male subgroup. In line with the
hypothesis of a proneurogenic effect of the postsynaptic 5-HT1AR, our studies seem to confirm
a leading role of this receptor in adult hippocampal neurogenesis. Future behavioral and
immunohistochemical studies are under way to identify the phenotype of newborn cells and the
influence of 5-HT1AR stimulation on the found alterations.
(1) Freie Universität Berlin - Germany | (2) Max Delbrueck Center for Molecular Medicine - Germany
Sander Svenja E | [email protected]
IS VISUAL AWARENESS A GRADED PHENOMENON? EVIDENCE FROM ERPS
Tagliabue, Chiara, F (1) | Mazzi, Chiara (1) | Savazzi, Silvia (1)
What we call consciousness (or awareness) refers to the fact that, when we are awake, we have
experiences. In visual cognitive neuroscience the debate on consciousness is now focused on
two major topics: the search for the neural correlates of visual awareness and the graded vs
dichotomous nature of visual conscious experience.
The project aim is to search for the possible neural correlates of different grades of visual
awareness in healthy subjects by investigating the ERPs to reduced contrast visual stimuli. It
can be hypothesized that different grades of awareness may be reflected by different
amplitudes of the components related to conscious perception.
The experiment includes two consecutive sessions. The first one is a threshold assessment, to
find two individual luminance values (one lighter and one darker) at which subjects (N = 12)
are aware of about 50% of the stimuli. Once the threshold is determined, in the second stage
subjects are presented with the same luminance values and required to judge the brightness of
the stimulus (lighter or darker) and then to rate the clarity of their perception on the 4-point
Perceptual Awareness Scale (no experience, brief glimpse, almost clear experience, clear
experience), while the EEG signal is recorded.
ERP analyses reveal a negative deflection peaking at 280-320ms from stimulus onset, probably
related to phenomenal awareness of the stimulus (the actual content), followed by a positive
deflection peaking at 500-600ms from stimulus onset, probably reflecting access to such
phenomenal content. Interestingly, both deflections show a reliable (p <= 0.05) amplitude
linear modulation related to the level of awareness: as visual awareness increases also the
amplitudes of the components increase.
It thus seems that the use of graded measures can actually tap different levels of visual
conscious experience.
(1) Department of Neurological and Movement Sciences - University of Verona - Italy
Tagliabue Chiara F | [email protected]
PROCESSING OF MULTI-DIGIT ADDITIONS IN HIGH MATH-ANXIOUS
INDIVIDUALS: AN EVENT-RELATED POTENTIAL STUDY
Núñez-Peña, María Isabel (1) | Suárez-Pellicioni, Macarena (1)
In the present study we investigated the time course of neural processing of multi-digit
additions in high- (HMA) and low-math anxious (LMA) individuals. Seventeen HMA and 17 LMA
individuals were presented with two-digit additions and were asked to perform a verification
task. Behavioral data showed that HMA were slower and more error prone than their LMA peers,
and that incorrect solutions were solved slower and less accurately that the correct ones.
Moreover, HMA individuals tended to need more time and commit more errors when having to
verify incorrect solutions than correct ones, as compared to their LMA peers. ERPs time-locked
to the presentation of the addends (calculation phase) and to the presentation of the proposed
solution (verification phase) were also analyzed. In the two phases, a P2 component of larger
amplitude was found for HMA individuals as compared to their LMA peers. Moreover, in the
verification phase, LMA individuals showed a larger late positive component (LPC) for incorrect
solutions at parietal electrodes as compared to their HMA counterparts. Because the P2
component is considered to be a biomarker of the mobilization of attentional resources towards
emotionally negative stimuli, these results suggest that HMA individuals might invest more
attentional resources during the arithmetical task than their LMA peers. Moreover, the smaller
LPC shown by HMA individuals when verifying incorrect solutions suggests that these solutions
might have been more plausible for them than for LMA ones.
(1) University of Barcelona - Spain
Suárez-Pellicioni Macarena | [email protected]
INVOLVEMENT OF NMDA RECEPTORS IN THE EFFECTS OF SOCIAL STRESS
ON SENSITIZATION TO THE PSYCHOMOTOR PROPERTIES OF COCAINE
Aguilar, Maria, A (1) | Garcia-Pardo, Maria, P (1) | Calpe-Lopez, Claudia (1) | Manzanedo,
Carmen (1) | Ledesma, Juan, C (1) | Miñarro, Jose (1)
Stress is a risk factor for drug consumption and relapse. In animal models, exposure to stress
induced by repeated social defeat (RSD) increases the rewarding and psychomotor effects of
cocaine. Our aim was to evaluate the involvement of glutamate NMDA receptors in the effects
of RSD on sensitization to the psychomotor properties of cocaine in mice. RSD consisted of four
encounters (PND 47-50-53-56) in which the experimental mouse was introduced into the cage
of an aggressive opponent mouse for 25 min (5 min free interaction). In the control groups,
mice were introduced into a cage without an opponent and were allowed to explore for 25 min.
To evaluate the development of sensitization, mice were pre-treated for 3 days with saline or
25 mg/kg of cocaine nine weeks after RSD or exploration. After 5 days, the animals were
challenged with cocaine (10 mg/kg) and tested in an actimeter. Twelve groups were assessed
according to the treatment received before RSD or exploration (saline, memantine) and the
pre-treatment received before cocaine challenge: Sal-RSD-Sal, Sal-RSD-Coc, Mem5-RSD-Sal,
Mem5-RSD-Coc, Mem10-RSD-Sal, Mem10-RSD-Coc, Sal-EXP-Sal, Sal-EXP-Coc, Mem5-EXP-Sal,
Mem5-EXP-Coc, Mem10-EXP-Sal, Mem10-EXP-Coc. Mice pre-exposed to the drug displayed more
hyperactivity than those pre-treated with saline, which confirmed the induction of sensitization.
Moreover, among the mice treated with saline before RSD or exploration, those exposed to RSD
were more hyperactive than those exposed to exploration, which indicated the existence of
cross-sensitization between RSD and cocaine. Memantine prevented the effects of RSD stress
on cocaine-induced hyperactivity and the development of cross-sensitization between RSD and
cocaine. This implicates NMDA receptors in RSD-induced potentiation of the psychostimulant
properties of cocaine.
Acknowledgements: MINECO, Dir.Gen.Inv, PSI2011-24762, PSI2014-51847-R; Inst.SaludCarlosIII,
RTA RD12/0028/0005; Unión Europea, Fondos FEDER “una manera de hacer Europa”. Ministerio
Sanidad, Delegación Gobierno PNSD, Proyectos Investigación Drogodependencias, 2014I007.
Generalitat Valenciana, Consell.Educación, PROMETEOII/2014/063, VALi+d for MP G-P.
(1) Unidad de Investigación Psicobiologia de las Drogodependencias - Departamento de Psicobiología Facultad de Psicología - Universidad de Valencia - Spain
Aguilar Maria A | [email protected]
CONTRIBUTION OF STRIATAL ASTROCYTES TO INTRASTRIATAL PROCESSES
SUBSERVING COCAINE SEEKING HABITS
Fouyssac, Maxime. (1) | Puaud, Mickaël. (1) | Page, Guylène. (2) | Everitt, Barry, J. (3) |
Janet, Thierry. (2) | Belin, David. (1)
Cocaine addiction has been suggested to result from loss of control over maladaptive drug
seeking habits. At the neural level, the transition from volitional drug use to drug seeking habits
is subserved by a shift in the locus of control over behaviour from the nucleus accumbens to
the dorsolateral striatum.
At the molecular level, the spread of adaptations from the ventral to the dorsolateral striatum
over the course of cocaine exposure has been associated with alterations of the expression of
the dopamine transporter (DAT), the target of cocaine. Whereas these alterations have been
considered to be related to neuronal mechanisms, the DAT is also expressed in astrocytes. We
have therefore investigated whether decreases in DAT protein levels following cocaine exposure
is neuronal, or instead be attributable to adaptations in astrocytes.
Rats were exposed either to short term cocaine self-administration under continuous
reinforcement or to three weeks of training under a second order schedule of cocaine
reinforcement. Whereas instrumental seeking performance under the former procedure is
underlined by nucleus accumbens-dependent goal-directed processes, it is instead subserved
by dorsolateral striatum-dependent stimulus-response habits under the latter. These two
cocaine experienced groups were compared to a naive group and rats that had been trained to
lever press for food. Following training, brains were harvested and samples of various striatal
territories were processed either for western blotting (from micro-punches) or primary
astrocytes culture.
As compared to controls, cocaine exposed groups displayed a decrease in DAT protein levels in
the striatal territories the majority of which was attributable to the complete blunting of DAT
protein expression in astrocytes.
These data show that cocaine-induced intrastriatal adaptations in DAT protein levels may
reflect adaptations in astrocytes rather than in neurons, suggesting they may causally
contribute to striatal mechanisms underling cocaine seeking.
(1) Department of Pharmacology - University of Cambridge - UK | (2) CIMOTHEMA EA3808 - Université
of Poitiers - France | (3) Department of Psychology - University of Cambridge UK
Fouyssac Maxime. | [email protected]
GHRELIN RECEPTOR AGONISM IMPROVES INCREASING PERFORMANCE OF
RATS IN THE MORRIS WATER MAZE
Mahieu, Michel (1) | Van Craenendonck, Hansfried (1) | Ver Donck, Luc (1)
Rationale: Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor plays
a role in multiple physiological processes including appetite regulation, metabolism and, more
recently, dendritic spine architecture, long-term potentiation and cognition.
The objective was to determine the effect of a ghrelin receptor agonist on cognition using a
Morris water maze paradigm to assess spatial learning and long-term memory in rats.
Methods The apparatus consisted of a polyethylene circular pool (2 m diameter) filled with
opaque water (temperature 25 ± 1 ºC). An escape platform (15 cm diameter) was placed in one
of the four, virtually divided, quadrants of the pool, 2 cm below the water surface. A video
camera positioned above the pool was connected to a computerized video tracking system to
record the swim trajectory (EthoVision® XT9, Noldus). During the acquisition phase, rats were
trained for 4 consecutive days to locate the platform using spatial cues (3 trials per day, cut
off time 60 seconds). On day 7, the platform was removed and rats were allowed to swim for
60 seconds (probe trial). The image analyzer tracked the gravity point, latency to locate
platform, total distance travelled, swimming speed, percentage of time in the periphery and
in each quadrant. Compound A, a Ghrelin receptor agonist, was administered SC 30 min prior
to the first trial of each training day.
Results rats treated with compound A reached the platform faster than the vehicles controls
during the training days. In the probe trial they showed shorter latency to first platform crossing
and more platform crossings.
Conclusions These results demonstrate that ghrelin receptor agonism elicits pro-cognitive
effects in a spatial learning and memory test.
(1) Janssen Pharmaceutica-Belgium
Mahieu Michel | [email protected]
NOVEL APPROACHES TO REFINE ASSESSMENT OF ABUSE LIABILITY OF
PSYCHOACTIVE SUBSTANCES
Tessari, Michela (1) | Dacome, Lisa (1) | Gerrard, Philip, A (1) | Pilla, Maria (1)
Over recent years there has been increased attention to the area of abuse liability by regulatory
agencies. Abuse liability may represent a risk to the drug development portfolio, may lead to
project delay or termination and may limit patients’ access to medicines due to the increased
complexity in physician prescription process. The absence of abuse potential and of scheduling
of a novel drug may therefore represent a major medical advantage.
A key component in non-clinical abuse liability testing is the evaluation of a potential
withdrawal syndrome induced by abrupt cessation of chronic administration of the test
compound. To this end, we have recently validated a novel test procedure combining
behavioural observations and measurements of physiological parameters in the rat. The data
show that under the conditions used in these studies, cessation from chronic chlordiazepoxide
has a distinctive effect on behavioural and physiological parameters, demonstrating that the
procedure used is adequate for detecting withdrawal symptoms.
A coherent strategy to the abuse liability assessment is important and data from one core assay
can enlighten choices of study design for the entire package of studies. For example, drug
discrimination is a method in which animals indicate whether a test drug produces interoceptive
stimuli similar to those produced by a known drug of abuse. We have shown that animals fully
generalise for a Test Compound only after training with cocaine but not with other drugs of
abuse. These data were utilised to drive the choice of the training drug for a subsequent selfadministration study, providing a more accurate assessment of the true abuse potential of the
novel Test Compound. The studies described are aligned with the FDA, ICH, EMA guidelines for
abuse liability assessment of novel chemical entities and show practical and pragmatic
approaches to preclinical assessment in this complex area.
(1) Toxicology and Safety Pharmacology - Aptuit - Italy
[email protected]
Tessari Michela | [email protected]
BIPHASIC EFFECTS OF AMPHETAMINE ON PRO-SOCIAL ULTRASONIC
COMMUNICATION IN JUVENILE RATS
Engelhardt, Karl, A (1) | Schwarting, Rainer, KW (1) | Wöhr, Markus (1)
Rats emit different types of ultrasonic vocalizations (USV) which serve as situation-dependent
affective signals. In adolescent and adult rats, two major call types can be distinguished: 22kHz and 50-kHz USV. 22-kHz USV mainly occur in aversive situations, such as predator exposure,
and are assumed to serve an important communicative function as alarm calls. By contrast, 50kHz USV mainly occur in response to appetitive stimuli and/or situations, such as social
encounters or drugs of abuse. In addition, they are assumed to serve an important pro-social
communicative function since playback of these calls elicits social approach behaviour in the
recipient. However, inconsistent with such a communicative function are findings showing that
amphetamine (AMPH) enhances the emission of 50-kHz USV, but paradoxically reduces social
interaction in rats, most notably juvenile play. Therefore, we directly examined this
inconsistency by comparing dose-response effects of AMPH on 50-kHz USV production and
perception in juvenile rats. To this aim, five drug treatment conditions were tested in two
behavioural paradigms: A) Open Field, B) Playback of 50-kHz USV, with playback of NOISE
serving as an acoustic control. Consistent with previous findings, AMPH increased both
locomotor activity and 50-kHz call emission in the open field. These effects followed an
inverted U-shaped pattern, with the response blunted in animals treated with a high AMPH dose.
Most notably, AMPH also had biphasic effects on social approach behaviour towards 50-kHz USV
and avoidance behaviour following NOISE. Specifically, AMPH at moderate doses potentiated
whereas high dose AMPH disrupted social approach and avoidance compared to vehicle control.
In conclusion, these findings do not support the notion that AMPH has opposing effects on prosocial 50-kHz USV emission and social interaction in juvenile rats. Instead, our findings suggest
that AMPH has pro-social effects that might be best regarded as enhanced and/or impulsive
need for social contact.
(1) Philipps-University of Marburg - Germany
Engelhardt Karl A | [email protected]
SELECTIVE ATTENUATION OF STRESS-INDUCED BEHAVIOURAL AND
MOLECULAR CHANGES ACROSS THE BRAIN-GUT MICROBIOME AXIS BY
POLYUNSATURATED FATTY ACIDS
Pusceddu, Matteo, M. (1,2) | Nolan, Yvonne, M. (3) | El Aidy, Sahar (2) | Green, Holly, F. (3)
| Araffin, Nurbazilah (1) | Kelly, Phil (4) | Clarke, Gerard (1,2) | Cryan, John, F. (2,3) |
Dinan, Ted, G. (1,2)
Stressful life events can exert long-lasting changes in the brain and the brain-gut-microbiota
axis, increasing vulnerability to mental illness especially in females. Omega-3 polyunsaturated
fatty acids (PUFA) play a critical role in the development and function of the CNS. We
hypothesized that an eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (80% EPA, 20%
DHA) PUFA mixture improved stress-related behavioural and neurobiological responses both in
neurodevelopmentally normal animals and in animals who were exposed as pups to a maternal
separation paradigm.
EPA/DHA dose dependently reduced anxiety and depressive-like behaviour in the elevated plus
maze and forced swim test, respectively, in non separated (NS) rats. Furthermore, cognitive
performance in the novel object recognition task was improved by EPA/DHA treatment in NS
animals only. Notably, EPA/DHA high dose increased the translocation of glucocorticoid
receptors (GR) into the nucleus of NS rat hippocampus. In the same rats, we also investigated
the gut-microbiota composition as a mechanism through which PUFA had an effect on
behavioural and neurobiological responses. A shift in Bacteroidetes: Firmicutes was observed
between NS and MS and this was normalized by EPA/DHA treatment in MS rats. Moreover,
EPA/DHA treatment positively influenced the abundance of a specific spectrum of bacteria
involved in anti-inflammatory activity, both in NS and MS groups. Using cortical cell cultures,
we further showed that DHA reversed corticosterone (CORT)-induced bimodal effect on the
neuronal and astrocytes composition of these cultures which resulted in increased cellular
death as well as neuronal apoptosis. Interestingly, these changes were prevented by DHA
reversal effect on CORT-induced reductions in GR and BDNF expression levels.
In conclusion, this study advances our understanding on the role of PUFA as future preventive
strategies to counteract CORT-induced cellular changes and, supports the concept that PUFA
intake could represent a beneficial habit to reduce the risk of development of stress related
pathologies.
(1) Department of Psychiatry (2) Alimentary Pharmabiotic Centre - University College Cork - Ireland |
(3) Department of Anatomy & Neuroscience University College Cork - Ireland | (4) Moorepark Food
Research Centre Teagasc - Ireland
[email protected] | [email protected] | [email protected] | [email protected] | [email protected]
Pusceddu Matteo M. | [email protected]
SINGLE NEURON FIRING IN THE RAT AMYGDALA DURING SOCIAL
INTERACTIONS
Pibiri, Francesca (1) | Poulter, Steven, L (1) | Lever, Colin (1)
The high prevalence of Autistic Spectrum Disorders (ASD), the hypothesised role of the
amygdala in ASD, and the need for rodent, rather than primate, models of ASD, all suggest the
importance of examining the typical responses of amygdala neurons in rodent social interaction.
As a first step in characterising the rodent social amygdala, we pair Lister Hooded rats in an
apparatus where they are free to engage in a variety of positive social interactions (including
anogenital sniffing, face to face contacts, following, walking over, allogrooming), with typically
infrequent aggressive behaviours. The apparatus is a 40x40 cm wooden square box with the
wall height of 50 cm. We perform extracellular electrophysiological recordings from ensembles
of single neurons in the rat amygdala tested in various social and non-social conditions (e.g.
familiar rat vs empty cage, familiar rat vs novel rats). In addition, we simultaneously record
behaviour with images time-stamped in synchronization with the electrophysiological
recordings. Preliminary results show that there are pyramidal neurons in the rodent amygdala
which respond strongly to social interaction. To date we have conducted preliminary analysis
from 131 neurons (which fired ≥100 spikes per trial) from 3 recording sessions (2 x empty box
vs familiar rat in box; 2 rats; 1 x familiar vs novel rats in box). More than 20% of cells showed
changes in the firing rate when a familiar social stimulus was present. Furthermore, the data
from one rat revealed that about 20% of the cells increased their firing rate when exposed to a
novel compared to a familiar rat.
(1) Psychology Department - Durham University - Durham UK
Pibiri Francesca | [email protected]
THE ROLE OF METABOTROPIC GLUTAMATE RECEPTORS DURING
AMPHETAMINE SELF-ADMINISTRATION IN DIFFERENTIALLY-REARED RATS
Cain, Mary E. (1) | Arndt, David L. (1) | Garcia, Erik J. (1)
Differential rearing environments alter the response to rewards in rodents. However, the
neurobiological mechanism remains unclear. Previous research suggests that differential
rearing may alter dopaminergic function in regions of the mesocorticolimbic pathway.
Glutamatergic innervation to regions of the mesocorticolimbic pathway modulates dopamine
activity that contributes to reward sensitivity. Therefore, we hypothesize that differential
rearing is also altering glutamatergic function and that these glutamatergic changes result in
the dopaminergic variation between differentially reared rats. To begin to test this hypothesis,
the current experiments examined if differential rearing altered the function of a
predominately presynaptic metabotropic glutamate receptor, mGluR2/3, and a predominately
postsynaptic glutamate receptor, mGluR5, during amphetamine self-administration. Male
Sprague-Dawley rats arrived in the lab at 21 days of age and were assigned to enriched (EC),
isolated (IC), or standard (SC) conditions. At 52 days of age, rats were briefly trained to lever
press for sucrose. At approximately 58 days of age, rats were implanted with chronic indwelling
jugular catheters. Following surgery recovery, rats were trained to self-administer intravenous
amphetamine (0.1 mg/kg/infusion) on a FR-1 schedule during 60-minute daily sessions. After
reaching stable responding, rats were injected with three doses of the mGluR2/3 agonist, LY379268 (0, 0.3, and 1.0 mg/kg, i.p.), or five doses of the mGluR5 antagonist, MTEP (0, 0.3, 1.0,
3.0, and 5.0 mg/kg, i.p.) 30-minutes prior to sessions. The 1.0 mg/kg LY-379268 dose decreased
responding in EC compared to IC rats, but only early in the self-administration session. The 3.0
mg/kg MTEP dose attenuated amphetamine self-administration in EC rats while 5.0 mg/kg MTEP
attenuated amphetamine self-administration in all rats. Taken together, these results suggest
that differential rearing alters pre- and post-synaptic mGlu receptor functioning. The results
further suggest that isolation may decrease the sensitivity of mGlu receptors and ultimately
contribute to increased reward sensitivity and vulnerability to addiction.
Supported by: NIH grant R15 DA035435
(1) Department of Psychological Sciences - Kansas State University - United States
Cain Mary E. | [email protected]
TOWARDS PHARMACOLOGICAL VALIDATION OF THE NOVELTYSUPPRESSED FEEDING TEST IN THE RAT AS A MODEL TO PREDICT THE
TIME-COURSE OF ANXIOLYTIC DRUG ACTION.
Auber, Alessia (1) | Guidi, Alessia (1) | Poffe, Alessandro (1) | Corsi, Mauro (2) | Gerrard,
Philip, A (1)
Currently available animal models of acute anxiolytic/antidepressant drug action provide useful
tools for drug discovery, they do not, however, allow investigation of temporal aspects needed
for clinical efficacy which may require several weeks (e.g. Serotonin Reuptake Inhibitors).
The aim of our study was to validate pharmacologically the Novelty-Suppressed Feeding Test
(NSFT), which has been suggested to exhibit predictive validity for time-course of anxiolyticeffects.
Rats were food-deprived for 23 hours, placed into a novel environment containing food and the
latency to begin eating was recorded.
Acute injection of Diazepam (2mg/Kg, i.p., 1 hour before test) reduced latency to eat compared
to controls (n=5; one-tailed t-test p<=0.05). Both acute and chronic treatment with Fluoxetine
(10mg/Kg, p.o., 1 hour before test,1 or 28 days respectively) tended to increase latency to eat
compared to controls (n=5-6 or n=13-14, one-tailed t-test p=0.05 or 0.06 respectively). In
summary, the well-known anxiolytic effect of Diazepam has been observed in the NSFT. Acute
Fluoxetine induces an anxiogenic-like effect and this is in line with the exacerbation of anxiety
symptoms reported by humans after a single administration of Fluoxetine. Chronic Fluoxetine
treatment also induced an anxiogenic-like effect which is in contrast with the anxiolytic-effect
observed in humans following chronic administration. Several studies have investigated the
effect of chronic Fluoxetine in different animal models of anxiety and contrasting results were
observed. It has been demonstrated that chronic Fluoxetine elicits different changes in stressed
mice compared to normal animals. This suggests that the anxiolytic effect of Fluoxetine, and
therefore the predictive validity of NSFT, may need to be assessed in animals subjected to
manipulations inducing a pathological state. Further experiment evaluating the effect of acute
vs. chronic Fluoxetine in stressed rats will be needed in order to set-up an animal-model with
predictive validity for the time-course of anxiolytic effect.
(1) Translational Pharmacology-Aptuit-Italy | (2) In Vitro Pharmacology-Aptuit-Italy
Auber Alessia | [email protected]
BEHAVIOR AND ELECTROENCEPHALOGRAPHIC SEIZURE ACTIVITY IN THE
APP/PS1 MOUSE MODEL OF ALZHEIMER’S DISEASE: EFFECTS OF
LEVETIRACETAM
Raeymaekers, Leen (1) | Oyelami, T (1) | Ahnaou, A (1) | Dewachter, I (2) | Kemp, J (1) |
Drinkenburg, WH (1)
Behavioral symptoms as well as epileptiform activity are common among Alzheimer’s disease
(AD) patients. Electroencephalographic (EEG) and behavioral assessment in several AD
transgenic mice models have revealed the occurrence of hyperexcitability, spontaneous
seizures and frequent epileptiform spike-wave discharges (SWD) associated with abnormal
behavior. In the current study, 24-hrs EEG/EMG or video-EEG/EMG monitoring was used in the
APP/PS1 mouse model at the ages of 8 and 18 months to -1) quantify spontaneous seizure
activity, - 2) monitor epileptiform SWD provoked by pentylenetetrazole (PTZ) at 30 mg/kg i.p.;
and -3) evaluate the effectiveness of acute and sub-chronic administration of the antiepileptic
drug Levetiracetam (150 mg/kg s.c.) at reducing seizures and behavioral abnormalities.
At 8 months, APP/PS1 mice did not develop spontaneous seizures, however, they showed
increased sensitivity to PTZ-induced seizure-like behaviors compared to littermate controls.
PTZ caused severe generalized seizures that were associated with a significant increase in EEG
power within the 4-30 Hz frequency range. These changes were short lasting and rapidly
abolished. At 18 months, 35% of APP/PS1 mice expressed recurrent spontaneous, non-convulsive
seizures (30-40s duration) and 60% sharp epileptiform SWD spikes at shorter duration i.e. 0.3 6.0 s. The APP/PS1 displayed higher motor level during the dark phase, whereas the majority
of seizures were characterized by motor arrest accompanied by subtle myoclonic jerks.
Repeated Levetiracetam reduced the occurrence of the epileptiform episodes and the total
duration of episodes. Consistent with previous reports, our findings demonstrate the emergence
of an age-dependent susceptibility to a seizure phenotype in APP/PS1 mice, and support the
potential efficacy of Levetiracetam in partially normalizing hypersynchronized network activity.
Further behavioral assessment is underway to reveal whether interictal as well as ictal
behaviors can be linked to this APP/PS1 EEG-defined phenotype and to help translate animal
model findings to AD patients.
(1) Janssen Pharmaceutica Belgium | (2) Université catholique de Louvain Belgium
Raeymaekers Leen | [email protected]
DOPAMINE DEPLETION INDUCES A SHIFT FROM ACTIVITY-BASED TO
SEDENTARY SOURCES OF REWARD IN A DECISION MAKING TASK:
REVERSAL EFFECT BY CAFFEINE
Lopez-Cruz, Laura (1) | San Miguel, Noemí (1) | Carratalà, Carla (1) | Monferrer, Lidon (2) |
Correa, Mercè (1,3) | Salamone, John, D. (3)
The mesolimbic dopamine (DA) system plays a critical role in aspects of motivation such as
behavioral activation, exertion of effort, and effort-based decision-making. DA depletion has
been shown to induce anergia in effort-based decision tasks. Caffeine, the most consumed
psychostimulant in the world, acts as a non-selective adenosine receptor antagonist (A1/A2A
receptors). Due to the functional interaction and co-localization of adenosine and DA receptors
in striatum, caffeine is being investigated in relation to DA-regulated behaviors such as
locomotion or effort-based decision-making. In the present work, we evaluate the effect of
caffeine on anergia and motor suppression induced by the VMAT-2 inhibitor tetrabenazine (TBZ),
which produces DA depletion. Anergia was evaluated in a three chamber-t-maze task in which
animals can chose between engaging in physical activity (running on a wheel, RW) vs. more
sedentary activities such as consuming freely available sucrose pellets, or sniffing a non-social
odor located in the third arm. Another group of animals was tested for locomotion in the RW.
DA receptor-activity-related markers (pDARPP32-Thr75 and Thr34) were assessed after drug
administration using western blot. In the t-maze, control mice spent more time running and
less consuming sucrose or sniffing. Low doses of TBZ produced a shift in the relative preference
reducing selection of the reinforcer that involved vigorous activity, but increasing consumption
of a reinforcer that required little effort (sucrose) at doses that had no effect on independent
measures of appetite or locomotion in the RW. These results suggest that DA depletion produced
anergia, but did not impair the primary reinforcing effects of sucrose. Caffeine was able to
reverse TBZ-induced shift in preferences and motor suppression induced by high doses of TBZ.
These behavioral effects were parallel to DARPP32
synthesis and phosphorylation, suggesting a functional adenosine-DA interaction at the receptor
level that modulates motor and motivational processes.
(1) Area de Psicobiología- Universitat Jaume I -Castelló (Spain) | (2) Area de Didáctica Ciencias
Experimentales- Universitat Jaume I- Castelló (Spain) | (3) Behavioral Neuroscience DivisionUniversity of Connecticut- Storrs (CT USA)
| [email protected]
Lopez-Cruz Laura | [email protected]
THE SPATIAL RESOLUTION OF THE GRID CELL MAP DEPENDS ON THE
ENVIRONMENT
Jacob, Pierre-Yves (1) | Poucet, Bruno (2) | Save, Etienne (3)
Investigating entorhinal grid cells properties while the rats freely explore open-fields or other
2D spaces has led to the assumption that grid cells provide an invariant self-movement-based
map of the environment. Here we show that in a familiar 1D continuous environment (i.e. a
circular track) grid cells display a novel 1D regular map whose firing fields tend to be more
spaced than in the 2D hexagonal grid. Moreover, in such unidimensional space, both the
regularity of the map and the interfield distance are strongly influenced by a visual cue. By
revealing permanent modifications of the grid cell map in a continuous 1D environment, our
results indicate that the entorhinal grid map is less invariant than previously thought, and
strongly suggest that the external information is essential to shape grid cell spatial activity.
(1) UMR 7291 | (2) CNRS | (3) Université d'Aix Marseille - France
Sargolini Francesca | [email protected]
BEHAVIORAL DEVELOPMENT TRAJECTORIES FROM PRE-PUBERTAL TO
ADOLESCENCE AND ADULTHOOD IN THE LGDEL MOUSE MODEL OF
22q11.2 DELETION SYNDROME
Ciampoli, Mariasole (1) | Papaleo, Francesco (1)
A microdeletion of the chromosome 22 band q11.2 results in the so called 22q11.2 deletion
syndrome (22q11.2DS). By late adolescence/early adulthood one-third of patients with
22q11.2DS develop schizophrenia, making 22q11.2DS the most commonly known genetic
syndrome associated with this psychiatric disorder. In an effort to set the ground towards the
development of early detection and early intervention strategies relevant to schizophrenia, we
developed a set of preclinical tasks enabling to assess preadolescent-adolescent mice.
Particularly, we are applying this newly-developed battery of tasks to LgDel mutant mice that
carry the same 1.5 Mb deletion of the human 22q11.2DS. This mouse model is a unique tool to
validate and elucidate early developmental abnormalities relevant to schizophrenia. However,
no studies had so far checked the impact of the 22q11.2 microdeletion in behavioral phenotypes
from birth to adolescence in mice. We first set the best experimental conditions to characterize
Startle and Pre-Pulse Inhibition abilities from pre-pubertal to adolescent. Using these settings
we unraveled altered startle responses in the LgDel mice at pre-pubertal ages (postnatal day
P14) that ameliorated in early development from P19. Moreover, sensorimotor gating deficits
started to appear as early as P19 lasting throughout adulthood. Motor coordination assessed
with the Rotarod Test, instead revealed in LgDel mice motor deficits in pre-pubertal period
(P15-16), that disappeared from adolescence (P35). Next, we implemented a modified version
of the 5-Choice Serial Reaction Time Task to measure attentional control in adolescent mice.
Adolescent wild-type mice were able to acquire and perform this new paradigm, advancing
across the different stages and environmental manipulations in less than fifteen days (P24-36).
Overall, our experiments are starting to elucidate new ways to test in mice the developmental
trajectories of schizophrenia-relevant behavioral phenotypes. This will be important in the
context of the development of early diagnostic and therapeutic intervention in schizophrenia.
(1) Department of Neuroscience and Brain Technologies - Italian Institute of Technology - Genoa - Italy
Ciampoli Mariasole | [email protected]
SOCIAL BUFFERING EFFECTS IN EXTINCTION OF FEAR MEMORY
Górkiewicz, Tomasz (1) | Knapska, Ewelina (1)
Interactions with conspecifics can protect individuals from exaggerated physiological and
behavioral fear responses to challenging situations, and can consequently prevent the
development of anxiety disorders. The phenomenon, called social buffering, is well known in
humans. Recently, several studies have confirmed its existence also in rodents. Designing
animal models gives us a chance of searching for the underlying neurobiological mechanisms.
In the model we present here we investigate how the presence of a conspecific affects
extinction of conditioned fear. Before the experiments rats were housed in pairs. Then, all
animals were subjected to cued fear conditioning and, subsequently, to either fear extinction
or context exposure. The training was conducted in the shuttle-box divided by a perforated
transparent partition allowing the animals to see, hear and smell the neighbor, but not to
contact him physically. Then, the animals were tested separately or in pairs and the freezing
response was recorded as the measure of fear. We have compared the freezing level in the
animals that were: (1) exposed to the experimental context without fear extinction and tested
separately (2) fear extinguished and tested separately, (3) exposed to the experimental context
without fear extinction and tested with fear extinguished rats, (4) exposed to the experimental
context without fear extinction and tested with rats exposed to the experimental context
without fear extinction, (5) fear extinguished and tested with fear extinguished rats, (6) fear
extinguished and tested with the partner subjected to the footshocks. In rats tested in pairs we
have observed significantly lower level of freezing response comparing to the animals that were
not subjected to fear extinction and were tested separately. Interestingly, this effect was
observed irrespectively of the stress status of the partner rat. This model seems to be suitable
to study neuronal basis of social buffering in fear extinction.
(1) Department of Neurophysiology - Nencki Institute - Warsaw - Poland
Górkiewicz Tomasz | [email protected]
IMPAIRED EMOTIONAL BEHAVIOR OF BACHD RATS, A TRANSGENIC MODEL
OF HUNTINGTON’S DISEASE
Lamirault, Charlotte (1) | Leblanc-Veyrac, Pascale (1) | Riess, Olaf (2) | Nguyen, Huu Phuc
(2) | Doyère, Valérie (1) | El Massioui, Nicole (1)
Huntington’s disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG
repeat in the gene encoding huntingtin protein. At the very early symptomatic phase, before
motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence
in HD patients. Agitation, anxiety and irritability are often described but also depression and/or
apathy, associated with a lack of emotional control.
Emotional (dys)function and regulation still need to be characterized in patients and animal
models of HD. To study specifically emotional symptoms, we used the BACHD rat model of HD,
which expresses the full-length mutant huntingtin genomic DNA with 97 CAA/CAG repeats (YuTaeger et al. 2012).
We performed a phenotypic analysis at different ages (4, 12 and 18 months) with different tasks
measuring anxiety and emotional reactivity to aversive situations: 1) social interaction (SI)
measuring behavior when rats are facing an unknown conspecific, 2) light/dark box (LD)
measuring the ability to leave a dark safe place and enter an open lit place, 3) conflict test
(CT) between safety and motivation and 4) fear conditioning. The results obtained showed that
the anxiety level, whatever the genotype, increased with age. Interestingly, BACHD rats were
more anxious than WT rats in SI, LD and CT tasks. In fear conditioning, the youngest BACHD rats
(4 months) froze less to the CS presentation and to the conditioning context than WT rats, and
extinguished faster to repeated presentations of the CS alone. However, these differences were
not observed in aged rats (18 months).
These results suggest an altered emotional phenotype in early symptomatic transgenic BACHD
rats, reminiscent of the already described emotional symptoms in HD patients. This model will
allow going further in studying the neurobiological bases of neuropsychiatric symptoms in HD.
(1) Institut des Neurosciences Paris Saclay - Université Paris Sud - France | (2) Institute of Medical
Genetics and Applied Genomics University of Tuebingen - Germany
| [email protected] | [email protected] | [email protected]
Lamirault Charlotte | [email protected]
DOSE-DEPENDENT CHANGES IN EXPRESSION OF NEUROPLASTICITY
MARKERS AFTER KETAMINE TREATMENT
Ionescu, Irina, A (1) | Heiko, Stahl (1) | Andreas, Kremer (1) | Angelo, Ceci (1) | Roberto,
Arban (1) | Lothar, Kußmaul (1)
NMDA-R antagonists have been described as potential novel treatment options in the therapy
of treatment-resistant depression (TRD). The most promising candidate in this class is ketamine,
a non-competitive NMDA-R antagonist with early-onset and long-lasting antidepressant effects
after single intravenous administration in TRD patients. However, potential differences in the
mode of action of ketamine responsible for its clinical efficacy compared to other NMDA-R
antagonists, such as lanicemine or subtype-selective NMDA-R inhibitors (e.g. Ro25-6981,
Traxoprodil), are as yet poorly understood. One promising avenue of research in this respect is
investigating acute ketamine-evoked changes in glutamate release by glutamate voltammetry
and correlating these with expression of neuroplasticity markers and behavioral changes in a
time- and dose-dependent manner. Early-onset ketamine-elicited changes in neuroplasticity
have been described in preclinical studies in brain regions such as the prefrontal cortex (PFC)
and the hippocampus (HPC). As described, we observed a dose-dependent increase in locomotor
activity accompanied by a significant decrease in peEF2/eEF2 levels in the HPC already one
hour after ketamine treatment in CD1 mice. We did not observe changes in synaptic proteins
such as synaptophysin and BDNF, which have been postulated to provide the basis for the longlasting antidepressant-like effects of ketamine. These results hint at the existence of a timedependent hierarchy in ketamine-elicited changes in synaptic plasticity which requires further
investigation.
Acknowledgments
(1) Boehringer Ingelheim - Germany
Ionescu Irina A | [email protected]
PREDICTIVE BEHAVIORAL TRAITS OF INTER-INDIVIDUAL DIFFERENCES IN
COCAINE SELF ADMINISTRATION IN RATS
Dellu Hagedorn, Françoise (1) | Noe, Emilie (1) | Brerat, Anaïs (1) | Crespin-Thebault, Laura
(1) | Caille, Stéphanie (1) | Cador, Martine (1) | Ravanello, François (1)
Cocaine addicts are characterized by several cognitive deficits, such as poor decision-making.
However, these deficits could preexist in some individuals before drug consumption, thus
representing risk factors and vulnerability toward the development of addiction. Poor decisionmakers can be identified within a healthy rat population, like in humans, using a Rat Gambling
Task. They also display a combination of traits reminiscent of addiction, notably risk-seeking,
reward-seeking, impulsivity and behavioral inflexibility (Rivalan et al., 13). Here, we tested
the hypothesis that poor decision-making and/or related behavioral traits prior to any drug
exposure could be risk factors of addiction. Using intravenous cocaine self-administration, our
protocol aimed at revealing inter-individual differences toward cocaine at the initial
development of addiction, under a tightly controlled acquisition schedule and an alternative
choice. Then, we evaluated some key characteristics of addiction (hypersensitivity to rewarding
effects, motivation to take drug and reinstatement of self-administration after extinction).
Individual clustered into three categories: rats with high (24%), moderate (46%) or low cocaine
(30%) consumption. Our protocol appeared to be relevant for identifying risk prone individuals
at the earliest steps of cocaine self-administration. These individuals also presented all the
characteristics of addiction addressed in this study: high cocaine intake, higher sensitivity to
drug reinforcing properties and proneness to reinstate drug-seeking after extinction, as opposed
to individuals with a moderate or low intake. Most poor decision-makers had medium or high
cocaine self-administration, except. More interestingly, the levels of cocaine selfadministration could be more accurately predicted by subtle differences in poor decisionmaking related behavioral traits. By integrating multiple behavioral measures, our work
provides a promising framework for identifying causal neural substrates of vulnerability to
cocaine addiction.
(1) INCIA - UMR 5287 CNRS - University of Bordeaux FRANCE
| [email protected]
Dellu Hagedorn Françoise | [email protected]
MONITORING DOPAMINE TRANSMISSION IN THE RAT NUCLEUS
ACCUMBENS SHELL AND CORE DURING NOSE POKING AND LEVER
PRESSING FOR SUCROSE
Bassareo, Valentina (1) | Cucca, Flavia (1) | Frau, Roberto (1) | Lecca, Daniele (1) | Di
Chiara, Gaetano (1,2)
Several studies investigated the dopamine (DA) responsiveness in the nucleus accumbens (NAc)
shell and core during food self-administration (SA), but some discrepancies between results,
probably due to the different methodological procedures used in each study, are shown.
In order to clarify this issue we investigated by microdialysis assays the responsiveness of DA
transmission in the NAc shell and core in rats responding for sucrose, using two different operant
schedules: nose poking versus lever pressing.
In rats trained to respond for sucrose pellets by nose poking fixed ratio 1 (FR1) schedule,
dialysate DA increased in the shell but not in the core during active responding, as well as
during extinction in the presence of sucrose cues. Instead, rats responding for sucrose by lever
pressing FR1 schedule shown a strengthening of DA transmission either in the NAc shell and core.
Non-contingent sucrose presentation and feeding in nose poking and lever pressing FR1 trained
animals increased dialysate DA to a similar extent in both shell and core.
We can conclude that using the nose poking training, under FR1 schedule of responding, the
non-contingent sucrose feeding activates DAergic transmission in the shell and core, while, the
response-contingent feeding activates DA release selectively in the NAc shell, as a result of the
action of sucrose conditioned cues. At the opposite, in lever pressing trained rats, during
responding for sucrose we found an increase of DA in both areas as a result of the different
instrumental task required to obtain the reward.
These findings can explain most of the discrepancies existing in the literature on the
responsiveness of shell and core DA during food self-administration behavior.
(1) Department of Biomedical Sciences - University of Cagliari- Italy (2) CNR Institute of NeuroscienceCagliari Section
Bassareo Valentina | [email protected]
THE ROLE OF STRIATAL DOPAMINE IN VISUAL DISCRIMINATION AND
REVERSAL LEARNING IN THE RAT
Sala Bayo, Júlia (1) | Alsiö, Johan (1,2) | Young, Leanne (1) | Saksida, Lisa M. (1) | Bussey,
Tim J. (1) | Mar, Adam C. (1,3) | Robbins, Trevor W. (1)
Impaired cognitive flexibility in touchscreen-based reversal learning tasks has been linked to
schizophrenia, obsessive-compulsive disorder, drug addiction and Parkinson’s disease. Current
treatments for these conditions are mostly ineffective at improving such cognitive impairments
- in fact, pharmacological interventions acting e.g. at the D2 receptor may exacerbate
symptoms and affect overall performance on less taxing tasks such as visual discrimination. To
investigate the neural basis of cognitive flexibility and to identify targets for potential
therapeutics, valid animal tests of reversal learning are required. We have developed a
touchscreen-based serial reversal learning task for rats. Rats were trained to discriminate
between two stimuli (e.g. CS+ vertical bars, CS- horizontal bars) on a touchscreen to receive a
sucrose reward. Contingencies alternated (e.g. CS+ horizontal bars, CS- vertical bars) until rats
consistently completed each reversal within three days. Stable performance allowed for
pharmacology using within-subject design. Systemic injections of the dopamine D2 receptor
antagonist, raclopride, impaired performance on the task at 0.03 mg/kg; however, raclopride
treatment also delayed the acquisition of a novel visual discrimination even at low doses (0.01
mg/kg). We further investigated the neural basis of these systemic effects by local
microinfusions of dopaminergic agents into the striatum. These results further highlight the
importance of dopamine in both visual discrimination and reversal learning.
(1) Department of Psychology and Behavioural and Clinical Neuroscience Institute - University of
Cambridge - United Kingdom | (2) Department of Neuroscience - University of Uppsala - Sweden (3)
New York University Medical Center - USA
Sala Bayo Júlia | [email protected]
NON-SPATIAL AND SPATIAL ATTENTIONAL DISORDERS IN
DEVELOPMENTAL DYSLEXIA ARE LINKED TO A MAGNOCELLULAR-DORSAL
STREAM DEFICIT
Bertoni, Sara (1) | Varuzza, Cristiana (2) | Schneps, Matthew, H. (3) | Franceschini, Sandro
(1) | Ronconi, Luca (1) | Menghini, Deny (2) | Gori, Simone (1) | Vicari, Stefano (2) |
Facoetti, Andrea (1)
Although developmental dyslexia (DD) is frequently associate with non-spatial and spatial
attentional disorders, these deficits might result from the effects of reduced reading
experience on the DD brain. This study investigated non-spatial and spatial attention in DD
children, in chronological age and reading level controls. Alerting and filtering of irrelevant
lateral visual information were impaired in DD children not only in comparison to chronological
age but also in comparison to reading level, excluding the possible effect of reduced reading
experience on these non-spatial and spatial attentional disorders. Importantly, DD children
showed an impaired motion perception sensitivity suggesting a magnocellular-dorsal stream
disorder as the underlying neurobiological cause. Children with DD were impaired in motion
perception, alerting and spatial attention only near foveal vision. These results demonstrate
that the magnocellular-dorsal stream deficit in DD might impair both non-spatial and spatial
mechanisms of visual attention sub-served by widely distributed fronto-parietal neural
networks.
(1) Developmental and Cognitive Neuroscience Lab - Department of General Psychology - University of
Padua - Italy | (2) Neuroscience Department - Children's Hospital Bambino Gesù Research Hospital Rome - Italy | (3) Harvard University - Cambridge - US
Bertoni Sara | [email protected]
SOME NICOTINIC BEHAVIORAL EFFECTS OF TOBACCO SMOKE
CONSTITUENTS IN NONHUMAN PRIMATES
Desai, Rajeev I (1) | Sullivan, Katherine A (1) | Bergman, Jack (1)
Recent preclinical studies in rodents suggest that tobacco constituents other than nicotine (NIC)
also exhibit pharmacological properties that may play a role in maintaining tobacco
consumption. The present studies were conducted to evaluate, respectively, the NIC-like
discriminative-stimulus (Sd) and reinforcing effects of minor tobacco alkaloids [e.g.,
nornicotine (NOR), anabasine (ANA), anatabine (ANAT), myosmine (MYO), and cotinine (COT)]
in nonhuman primates. In drug discrimination (DD) studies, the ability of minor tobacco
alkaloids to engender NIC-like Sd effects was determined in squirrel monkeys (n=4) trained to
discriminate a highly potent NIC-like agonist [(+)-epibatidine; EPI] from vehicle. In IV selfadministration (SA) studies, second-order fixed-interval (SO-FI) schedule procedures in NHP
(n=3) were utilized to determine whether selected minor tobacco alkaloids (e.g., NOR, ANAT,
and MYO) exhibit NIC-like reinforcing effects. Results from DD studies show that: a) NIC and
minor tobacco alkaloids engendered full (NOR, ANA, MYO, ANAT), or no (COT) substitution for
EPI. Results from our SA studies show that NIC (0.0032-0.032 mg/kg/injection) reliably
produced dose-related IV SA behavior under the SO-FI schedule, with peak rates of responding
during availability of the unit dose of 0.01 mg/kg/injection. In contrast, NOR (0.032-0.18
mg/kg/injection) and ANAT (0.01-0.18 mg/kg/injection) produced response rates that are
between those engendered by nicotine and those during saline availability; MYO (0.32-5.6
mg/kg/injection) failed to maintain IV SA under the SO-FI schedule; response rates were no
greater than for vehicle. Taken together these findings suggest that non-NIC tobacco
constituents may differentially produce nicotine-like addiction-related effects that contribute
towards maintaining long-term tobacco consumption (DA-031231 - NIDA/NIH).
(1) Preclinical Pharmacology Program - Harvard Medical School - McLean Hospital - USA
Desai Rajeev I | [email protected]
EFFECTS OF AGE AND EXPERIENCE ON EPISODIC MEMORY DEVELOPMENT
IN THE RAT
Gutoreva, Alina (1) | Lyon, Stephanie, A (1) | O'Dioluin, Brian (1) | Langston, Rosamund, F
(1)
Episodic memory is richly detailed memory for unique events. In humans it develops relatively
late in childhood and it is early to decline in neurodegenerative disorders such as Alzheimer’s
disease and Huntington’s disease. The developing rodent model provides a unique opportunity
to study the emergence of distinctive memory subtypes and whether they mirror the
differential development of memory subtypes in human infants. Whilst rats are most commonly
used to study episodic memory, extremely little is known about its ontogeny in this species.
The aim of the current study was to investigate the time points at which the essential
components contributing to episodic memory develop and the contribution of experience or
mental schema to this timecourse. Employing different recognition memory tasks based on
intrinsic novelty preference, we explored the emergence of memory for objects, object
location, and the background context in which objects appear. To examine episodic memory,
a task that combined all these three components was used. Two studies were carried out. In
the first, we examined the effect of age only on episodic memory development using a crosssectional between subjects design. In the second, we assessed the effects of experience by
conducting a longitudinal within subjects experiment. Preliminary results suggest that memory
for objects, places and contexts develop at different ages as seen in human children.
Experience led to an earlier emergence of memory for object location and of episodic memory,
but not the other types of memory. Ongoing analysis will attempt to examine the relative
contributions of recollection and familiarity to memory processing in these behavioural tasks.
(1) Division of Neuroscience - University of Dundee Scotland UK
[email protected]
Gutoreva Alina | [email protected]
PHARMACOLOGICAL MANIPULATION OF THE CHOLINERGIC SYSTEM FOR
COGNITIVE ENHANCEMENT IN YOUNG HEALTHY RATS.
Fisher, Beth, M (1) | Mar, Adam, C (2) | Robbins, Trevor, W (1)
Rationale: Targeting of the cholinergic system for cognitive enhancement in young, healthy
individuals is of interest for the development of ‘smart drugs’. Further research is required to
establish the neuropharmacological and behavioural mechanisms underlying the putative
cognitive enhancing effects of the acetylcholinesterase inhibitor donepezil in this population.
Method: The current experiments investigated the effects of donepezil (0-1 mg/kg, i.p.) in
healthy young rats on the 5-Choice Serial Reaction Time Task (5-CSRTT) which measures spatial
divided attention for visual detection and on the novel touch-screen based rodent Continuous
Performance Task (rCPT) which measures sustained, focused attention for visual identification.
The ability of non-selective nicotinic receptor antagonist, mecamylamine (1mg/kg, i.p.),
pretreatment to modulate the effects of donepezil (1mg/kg, i.p.) was also assessed. Drug
manipulations were testing on stimulus duration probes of 125, 250 and 500ms on the 5-CSRTT
and of 200, 600 and 1000ms on the rCPT.
Results: Donepezil-induced enhancements in cognitive performance (% accuracy) on the 5CSRTT were observed reliably only in the context of mecamylamine impairment. By contrast,
on the rCPT, donepezil alone showed a linear trend for enhanced performance (increased hit
rate and d’prime) in a dose-dependent related manner during longer stimulus durations.
Significant enhancements in task performance (decreased false alarm rate) following donepezil
administration were also observed in the context of mecamylamine pretreatment, which itself
had no effect on donepezil-induced enhancements on rCPT performance per se.
Discussion: These findings suggest that donepezil may enhance aspects of attention in young,
healthy subjects as measured on the rCPT, whilst enhancing impaired subjects in the case of
the 5-CSRTT. These findings highlights the potential of the touchscreen-based rCPT task as a
promising new sensitive behavioural tools for assessing enhancements of cognition in young
‘healthy’ subjects.
(1) Behavioural and Clinical Neuroscience Institute (BCNI) - Department of Experimental Psychology University of Cambridge - Cambridge - CB2 3EB | (2) Department of Neuroscience and Physiology New York University Medical Centre - New York - NY 10016
Fisher Beth M | [email protected]
FASTING INCREASES AND SATIETY DECREASES MEMORY PERFORMANCES
IN WISTAR RATS
Canova, Vincent (1) | Palouzier-Paulignan, Brigitte (1) | Ravel, Nadine (1) | Thevenet, Marc
(1) | Romestaing, Caroline (2) | Julliard, Karyn (1)
Growing evidence exists for a strong link between energy balance and memory both in human
and rodents. Consuming high-energy diets promoting obesity leads to cognitive deficits whereas
a caloric restriction improves memory performance. This interplay between cognitive functions
and nutrition seems to be mediated by a direct action of endocrine and metabolic molecules
on the hippocampus. However, changes in memory performance according to feeding state
(before vs after the meal) have never been investigated in rodents. In the present study, we
used two strains of young adult rats: (i) Wistar rats and (ii) lean obesity-resistant Lou/C rats
which in contrast to Wistar rats, does not display any fluctuation of the main orexigenic and
anorexigenic peptides in hypothalamus. The influence of feeding state on memory
performances of these two rodent strains was assessed using a behavioral paradigm based on
spontaneous odor novelty recognition. In the present study, we have shown that Wistar rats
displayed a better recognition memory when they were fasted than when they were satiated.
Interestingly, Lou/C rats exhibited high memory performances regardless of the feeding state.
Investigating the molecular mechanisms involved in these memory capacities differences, we
showed that molecules regulating food intake and their receptor are indeed modulated
according to feeding state in hippocampus. Taken together, our results suggest that daily
physiological fluctuations of signals known predominantly to be associated which endocrine and
metabolic regulation, can have a strong influence on higher brain functions such as memory.
(1) Lyon Neuroscience Research Center - Inserm U1028 - CNRS 5292 - University Lyon 1 - France | (2)
Laboratory of Ecology of Natural and Anthropized Hydrosystems - CNRS 5023 - University Lyon 1 France
Canova Vincent | [email protected]
HYPERACTIVITY DEVELOPING IN CD-1 MALE MICE FOLLOWING CHRONIC
SOCIAL DEFEAT STRESS
Galyamina, Anna G. (1) | Kovalenko, Irina, L (1) | Smagin, Dmitry, A. (1) | Kudryavtseva,
Natalia, N (1)
Chronic social defeat stress as an etiologic factor is widely used for the production of
depression-like states in mice. However, different effects of social stress were shown in the
mice of different strains and even in the animals of one strain. Considering these data and
recognizing the importance of the outbred CD-1 mice for numerous research areas, in this work
we describe the effects of chronic social defeats stress* on male mice of this strain. Defeated
mice (losers) in first intermale confrontations demonstrated the active defense during attacks
of aggressive partners. Thereafter the behavior of the losers transformed to the passive
behavior (immobility, freezing and waiting). Pronounced anxiety as estimated by scores of the
plus-maze test and decreased communicativeness estimated as decreased behavioral reaction
to a partner in the partition test were found in the losers. An increased time of immobility,
which can indicate the development of a depression-like state was revealed in the Porsolt test.
Additionally, CD-1 losers displayed locomotor hyperactivity and increased exploratory activity:
an increased number of rearing and crossed squares in the open-field test and increased the
number of passages and total entries in the plus-maze test. Thus, chronic social defeat stress
is accompanied by the comorbidity of hyperactivity with pronounced anxiety and
depressiveness, developing in defeated CD-1 mice. Hyperactivity is considered as symptom of
bipolar disorder, which is characterized by alternate episodes of depression and mania. We
think that outbred CD-1 mice demonstrating several patterns of mania- and depression-like
state simultaneously following chronic social defeat stress may be used as a potential model of
bipolar disorder.
*Kudryavtseva et al. Social model of depression in mice of C57BL/6J strain. Pharmacol.,
Biochem. Behav. (1991) 38(2), 315-320.
Supported by Russian Scientific Foundation, no. 14-05-00063.
(1) Institute of Cytology and Genetics SD RAS - Russia
Galyamina Anna G. | [email protected]
DECREASED SYNAPTIC PLASTICITY AND PFC-DEPNDENT COGNTIVE
FUNCTIONS IN ADOLESCENT MICE
Sidiropoulou, Kyriaki (1) | Konstantoudaki, Xanthippi (1) | Chalkiadaki, Kleanthi (1)
Adolescence is considered a highly vulnerable period, as it coincides with the occurrence of
several major psychological disorders, such as schizophrenia, depression, eating disorders and
emotional disorders. During the adolescent period, several behavioral changes occur, such as
increased social interaction, risk taking behavior, as well as spontaneous novelty seeking. The
prefrontal cortex (PFC) is a brain area involved in the above-mentioned functions as well as in
other higher-order cognitive process. The PFC is thought to reach maturation later than other
cortical areas, a conclusion based primarily on structural data of dendritic morphology.
However, there is still very little information regarding the functional changes in the PFC that
are on going during postnatal development, and particularly during the adolescence period.
Our aim in this study is to investigate, first, the cognitive behavior of adolescent mice compared
to adults, and subsequently, the physiology that underlies the adolescent behavior. Our results
show that adolescent mice perform poorer in PFC-dependent cognitive tasks, such as the
delayed alternation in the T-maze and the temporal order object recognition memory task,
compared to non-PFC dependent tasks, such as the novel and object-to-place recognition task
compared to adult mice. Furthermore, we find that adolescent mice exhibit decreased longterm potentiation in layer II synapses of the PFC, but not the barrel cortex, and decreased spine
density. A more detailed age-dependent analysis of LTP and dendritic spine density shows that
there is a peak of plasticity just before the beginning of adolescent period, suggesting that
synaptic pruning and maturation of neuronal circuits in the prefrontal cortex occurs at this
sensitive time period.
In conclusion, our results show that adolescence is a time-period during which behavioral and
physiological changes occur specifically in the PFC, which could justify the increased
vulnerability to stress, drugs of abuse and emergence of neuropsychiatric disorders.
NMDA LESIONS OF THE PVT DO NOT DIFFERENTIALLY AFFECT FORCED
SWIMMING IN MALE RATS
Tunckol, Elcin (1) | Alpat, Basak (2) | Temel, Zeynep (2) | Oz, Pınar (3) | Sireci, Siran (2) |
Gokcelioglu, Gorkem (2) | Canbeyli, Resit (2)
In mapping the brain structures involved in an animal model of depression, namely, forced
swimming, we have shown that depression as measured by increased immobility in the second
of two consecutive swim tests is ameliorated by bilateral lesions of the central nucleus of the
amygdala (CEA) and the suprachiasmatic nucleus (SCN), but aggravated by lesions of the bed
nucleus of the stria terminalis (BNST). The paraventricular nucleus of the thalamus (PVT), a
midline thalamic nucleus, is known to respond to repeated stressors including swimming.
Moreover, PVT is connected with structures that modulate depression induced by forced
swimming, including the SCN, BNST and the CEA. The present study therefore investigated the
effect of lesioning the PVT in forced swimming tests (FSTs). Adult male Wistar rats subjected
to 3 μl NMDA ( Sigma) lesions (5.88 ųg/ųl in saline ) in mid-PVT region (n=14) or to sham lesions
(3 μl saline; n=10) were subjected a week later to a 15-min FST followed by a 5-min FST 24 hr
later. Analysis of Variance indicated that the lesioned and sham groups displayed comparable
durations of immobility in FST2 (81.2 ± 15.9 sec and 62.6 ± 9.6 sec, respectively). Subsequent
open field and elevated plus maze tests did not reveal a differential effect of PVT lesions. The
present results suggest that lesions of mid-PVT region may not play a decisive role in forced
swimming and anxiety. Further research targeting the anterior and posterior regions of PVT
that display differential connectivity with stress-related brain structures may reveal a more
specific role for the PVT in depression.
(1) The Institute of Biomedical Engineering - Bogazici University - Istanbul - Turkey | (2)
Psychobiology Laboratory - Psychology Department - Boğaziçi University- Istanbul-Turkey | (3)
Neuropsychopharmacology Research and Application Center - Üsküd
Tunckol Elcin | [email protected]
EFFECTS OF CANNABINOIDS ON COGNITIVE BEHAVIOR IN NONHUMAN
PRIMATES
Kangas, Brian D. (1) | Leonard, Michael Z. (1) | Bergman, Jack (1)
The primary psychoactive ingredient of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC), has
medicinal value but also produces unwanted effects on cognitive function, promoting the search
for novel, improved cannabinergic therapeutics. The present studies used touchscreen
procedures in nonhuman primates to compare the effects of different types of cannabinergic
drugs on several measures of performance including learning (repeated acquisition), cognitive
flexibility (discrimination reversal), short-term memory (delayed matching-to-sample),
attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included
the CB1 partial agonist Δ9-THC, the CB1 full agonists AM4054 and WIN 55,212-2, the
endocannabinoid anandamide, and its stable synthetic analog methanandamide. The effects of
Δ9-THC and anandamide after treatment with, respectively, the CB1 inverse agonist/antagonist
SR141716A and the FAAH inhibitor URB597, also were examined. Results show: a) Δ9-THC, WIN
55,212-2, and AM4054 produced dose-related impairments of discrimination-based cognitive
behavior
with
potency
that
varied
across
tasks
(discriminative
capability<=learning<=flexibility<=short-term memory); b) anandamide alone was without
effect on all endpoints; c) anandamide following URB597 pretreatment and, as well,
methanandamide had negligible effects on discriminative capability, learning, and flexibility,
but significant, though moderate, effects on short-term memory; d) all drugs, except
anandamide, disrupted attention in a dose-related manner; e) progressive ratio breakpoints
were generally unaffected by all drugs tested, suggesting little-to-no effect on motivation.
Taken together, these data indicate that: 1) cognitive endpoints are differentially vulnerable
to CB1 action, and 2) metabolically stable forms of anandamide may have lesser adverse effects
on cognitive functions than other CB1 agonists, possibly offering a therapeutic advantage over
other CB1 agonists in clinical settings.
(1) Harvard Medical School - McLean Hospital - United States
Kangas Brian D. | [email protected]
IN VIVO DOPAMINE AGONIST PROPERTIES OF ROTIGOTINE: ROLE OF D1
AND D2 RECEPTORS
Fenu, Sandro (1) | Espa, Elena (1) | Pisanu, Augusta (2) | Di Chiara, Gaetano (1,2)
Rotigotine acts in vitro as a full agonist of dopamine D1 receptors at concentrations almost
superimposable to those at which it acts at D2 receptors. However in vivo evidence of D1 agonist
activity of rotigotine has not been yet provided. In order to test the ability of rotigotine to
stimulate dopamine D1 and D2 receptors in vivo we studied the effect of SCH 39166 and
eticlopride, selective dopamine D1 and D2/D3 receptor antagonists, respectively, on rotigotineinduced contralateral turning behavior in rats bearing unilateral 6-hydroxydopamine lesions of
dopamine neurons. In the same model we tested the ability of rotigotine to stimulate the
expression of the immediate-early gene c-Fos in the caudate-putamen, an in vivo marker of D1
receptor activity. As comparison we tested in parallel the D2/D3 agonist pramipexole. In primed
6-hydroxydopamine lesioned rats rotigotine (0.035, 0.1 and 0.35 mg/kg s.c.) induced a dosedependent contralateral turning behavior that was reduced by SCH 39166 and eticlopride after
doses of rotigotine of 0.1 mg/kg s.c. In drug-naive rats rotigotine was less effective in inducing
contralateral turning and SCH39166 reduced it. Pramipexole induced contralateral turning in
primed but not in unprimed rats and this turning was potentiated by SCH 39166 and abolished
by eticlopride pretreatment. Rotigotine induced c-Fos expression in the caudate-putamen and
SCH 39166 blocked it completely. Pramipexole failed to induce c-Fos expression. These results
show that rotigotine act in vivo as a D1/D2 agonist, in contrast with pramipexole that is devoid
of D1 activity in vivo. These observations would predict that the rotigotine and pramipexole
might also differ in their spectrum of application to the therapy of Parkinson’s disease.
(1) Department of Biomedical Sciences - University of Cagliari - Cagliari - Italy | (2) National Research
Council of Italy - Neuroscience Institute - Cagliari Section - Cagliari Italy
Fenu Sandro | [email protected]
ANALYSING THE UTILITY OF THE NOVEL OBJECT RECOGNITION ASSAY IN
RATS
Ernyei, Aliz, J. (1) | Kassai, Ferenc (1) | Plangár, Imola (1) | Gyertyán, István (1)
Novel object recognition (NOR) task is a widespread, attractive model for investigating visual
recognition memory in rodents. However, as the assay lacks any executive component it is very
sensitive to the actual state of the animals and environmental conditions including the objects
themselves.
Our aim was to analyse the stability of NOR with regard to strain differences, object preference
and repetition coherence.
Exploration times were measured for three object pairs with 80 min intertrial delay in four rat
strains. To reveal object preference discrimination indices (DI) were separately calculated
when the novel object was one or the other of the pair.
Hannover Wistar (HanW), Charles-River Wistar (CrlW) and Charles-River Long-Evans (ChLE) rats
disparately discriminated the G and O object pair (DIs were 0.42, 0.25 and 0.26, respectively).
However, while the Wistar strains showed more or less balanced interest towards objects G and
O, ChLE clearly preferred G (DI(Gnew)=0.35, DI(Onew)=0.03). Similar inconsistencies were
found with another pair of objects (C and T), where CrlW and HanW showed similar and modest
overall DI (0.17, 0.18) with a clear preference for T in HanW (DI(Tnew)=0.26, DI(Cnew)=0.09)
but not in CrlW. Janvier Long-Evans rats (JLE) discriminated T and C much better (DI=0.41),
however, with an underlying preference to C (DI(Cnew)=0.56, DI(Tnew)=0.11). On a re-test trial
a month later, this preference was still observed though shrank (0.44 and 0.2 DI values), while
individual DIs did not correlate (r=0.2, p>0.05). Finally, the pair of S and P objects markedly
differed in their discriminability in CrlW (0.01) and JLE (0.4).
Due to the considerable strain/supplier differences in object preference and object
discriminability and the lack of intraindividual coherence, a particular NOR test procedure
established in a specific strain and with specific, carefully selected objects may not work under
other conditions.
(1) MTA-SE NAP B Behavioural Pharmacology Group - Hungary
Ernyei Aliz J. | [email protected]
FUNCTIONAL HETEROGENEITY AMONG MIDBRAIN DOPAMINE NEURONS IN
THE CONTROL OF CUE ATTRACTION, CONDITIONED LOCOMOTION, AND
REINFORCEMENT
Janak, Patricia, H
The specific nature of dopamine’s (DA) role in motivated behavior is a matter of debate. This
is due in part to the anatomical complexity of the system, where neurons in the more medial
ventral tegmental area (VTA) project largely to the prefrontal cortex and nucleus accumbens,
while neurons in the more lateral substantia nigra (SN) project to the dorsal striatum. To parse
the contribution of these distinct subpopulations to different facets of appetitive motivation
and learning, we targeted expression of channelrhodopsin to dopaminergic neurons in TH::cre
rats. Pavlovian Conditioning: TH::Cre+/- rats first received Pavlovian training, in which blue
laser was delivered unilaterally to either the VTA or SN, independent of behavior. For PAIRED
rats, this stimulation was predicted by the presentation of external cues, while for UNPAIRED
rats cues and stimulation were unassociated. We found that, across training, different
conditioned responses to the Pavlovian cues emerged for VTA and SN stimulation. PAIRED, but
not UNPAIRED, rats receiving the most medial VTA stimulation developed cue-light approach
behavior, suggesting the cue had become attractive. Cues predictive of SN laser delivery
elicited locomotion in response to the cue, expressed as rotation contralateral to the
hemisphere of laser delivery, but no approach. Conditioned Reinforcement: Rats were given
the opportunity to lever press for cues in the absence of laser delivery and responded robustly
for VTA, but not SN paired cues. Intracranial Self Stimulation: Finally, rats were allowed to
nose poke for brief laser pulses. This self-stimulation behavior was robust regardless of laser
target site in the VTA and SN. Together, these results demonstrate that anatomically distinct
DA neuron subpopulations control the attribution of motivational value to neutral cues to spur
attraction, psychomotor activation, and support conditioned reinforcement, while the ability
of DA neurons to directly reinforce actions is relatively consistent throughout the midbrain.
Department of Psychological and Brain Sciences - Johns Hopkins University - Baltimore, MD 21218 USA
Saunders Benjamin T | [email protected]
AVERSIVE COUNTER-CONDITIONING: A BEHAVIORAL APPROACH TO
INHIBIT REINSTATEMENT OF EXTINGUISHED APPETITIVE CUES IN 5-HTT
KNOCKOUT RATS
Karel, Peter, GA (1) | Almacellas Barnbanoj, Amanda (1) | Kaag, Anne Marije (2,3) | Van den
Brink, Wim (3) | Reneman, Liesbeth (2) | Van Wingen, Guido (3) | Homberg, Judith, R (1)
Behavior of cocaine addicts is strongly driven by cocaine-related conditioned stimuli (CS) which
can evoke drug seeking behavior and are notoriously hard to extinguish using conventional
exposure therapy. Individuals characterized by low expression of the serotonin transporter (5HTT) show an increased sensitivity to conditioned environmental stimuli. Indeed previous
research has shown that the 5-HTT-/- rat exhibits an impaired extinction of cue-induced
cocaine-seeking behaviour. However, pharmacological manipulation of the extinction process
has only been moderately successful in these animals. In the current study we aimed to develop
an appetitive-aversive counter conditioning paradigm that increases extinction and decreases
reinstatement to reward associated cues. To that end we developed a 4 stage touch screen
visual discrimination task in which we can test the effectiveness of counter-conditioning versus
conventional extinction using a within-subject design. During the experiment rats are presented
with 3 visual stimuli in a modified 2 window visual discrimination task CS+, CS+cc and CS-.
During the first phase (conditioning) of the experiment responding to CS+ and CScc+ will be
rewarded with either a sucrose pellet or cocaine infusion. During the second phase responding
to CS+ becomes non-rewarding (extinction) and responding to CS+cc triggers a 0.25mA
footshock (counter-conditioning). During the third phase no CS will be rewarded (extinction)
until the behavior is fully extinguished. In the fourth phase the session is started with the
presentation of a large reward, but responding brings no further reward (reinstatement). Here
we will share our preliminary results in this set-up after using both sucrose and cocaine (under
long access conditions) as reinforcers.
(1) Donders Institute for Brain Cognition and Behaviour - Dept. of Cognitive Neurosci. - RadboudUMC the Netherlands | (2) Departement of Radiology - Academic Medical Centre Amsterdam - the
Netherlands | (3) Dept. of Psychiatry - AMC Amsterdam - the Netherlands
Karel Peter GA | [email protected]
A STUDY OF THE SELECTIVE 5-HT2C AGONISTS LORCASERIN AND
CP809101 ON MEASURES OF IMPULSIVITY AND FOOD REINSTATEMENT IN
THE RAT
Higgins, G, A (1) | Silenieks, L, B (1) | Altherr, E, B (2) | Patrick, A (1) | DeLannoy, I, A, M
(1) | Fletcher, P, J (3) | Pratt, W, E (2)
The 5-HT2C receptor agonist lorcaserin has been approved for obesity. Understanding the
neurobiological processes by which 5-HT2C receptor agonists treat obesity may improve clinical
outcomes by identifying patients who would benefit most from this pharmacological approach.
Current evidence supports three potential mechanisms for the anti-obesity effect of this drug
class, (1) control of hypothalamic signaling of peripheral gustatory inputs, (2) control of
rewarding/hedonic aspects of food, (3) regulation of motor impulsivity which may represent a
predisposing factor in multiple addictive behaviours including obesity.
Study purpose was to examine the third line of evidence by examining lorcaserin and the highly
selective 5-HT2C agonist CP809101 on 2 food motivated impulsivity tasks (5-CSRTT and delay
discounting), and on reinstatement of food motivated responding. Doses of each drug were
directly compared to doses necessary to affect feeding induced by hunger - a 22h food
deprivation model. We also evaluated plasma:CSF levels of LOR and CP at doses and timepoints
relevant to the in-vivo studies.
At doses significantly lower than those necessary to reduce deprivation-induced feeding (3-6
mg/kg SC), both CP and LOR reduced motor impulsivity and reinstatement of food responding
(0.03-1 mg/kg). For example, both LOR and CP significantly reduced premature responses
compared to vehicle control (VEH: 42+6, LOR 0.3 mg/kg: 15+5; CP 0.6 mg/kg: 21+4; P<=0.01)
in rats tested under a fixed 10s ITI schedule in the 5-CSRTT. The effects of LOR were at a dose
(0.03 mg/kg) which resulted in clinically relevant plasma exposures (30-50 ng/ml). Taken
together, these studies implicate clinical populations where obesity is linked to impulsivity trait,
such as binge eating disorder, as having potential to benefit from 5-HT2C agonist treatment.
(1) InterVivo Solutions - Canada | (2) Wake Forest University - USA | (3) CAMH - Canada
Higgins Guy A. | [email protected]
EVALUATION OF SYNTHETIC DERIVATIVES OF MEDIUM CHAIN
TRIGLYCERIDE (MCT) FATTY ACIDS IN MICE
Higgins, G, A (1) | Caskanette, J (1) | Patrick, A (1) | Lau, W (1) | Milgram, B (2) | Balenci, L
(3) | Andrews, J, S (3) | Annedi, S (4) | Araujo, J, A (1)
The MCT ketogenic (KG) diet is considered among the most effective therapies for certain
refractory epilepsies and has also been proposed to be of value for the treatment of pain and
inflammation conditions. The MCT KG diet contains medium chain fatty acids (MCFA) with
caprylic acid (CA8) and capric acid (CA10) being primary constituents. Acute treatment with
CA8 or CA10 increases blood levels of ß-hydroxybutyrate (ßHB) - a biomarker of ketosis, but
both compounds show very modest effects in mouse seizure models compared with synthetic
anti-epileptic drugs (AED’s) such as valproate. Recently Chang et al (JPET [2015] 352:43-52.)
described a novel series of synthetic derivatives of MCFA with evidence for improved tolerability
and efficacy compared to CA8 and CA10, and possible improvement over the MCT KG diet. The
present studies benchmarked a selection of these synthetic derivatives to CA8, CA10 and
acetone.
All compounds were evaluated across a standardized series of seizure tests (MES, scPTZ, 6Hz,
corneal kindling (CK)), a pain model (spared nerve injury), tests of side-effect (body
temperature, rotorod, motor activity) and blood ßHB levels conducted in male CD-1 mice.
Acetone, CA8 and CA10 showed a varying degree of efficacy in the MES, 6Hz and scPTZ tests
and increased blood ßHB level, but at doses that affected motor function (e.g. acetone ED50:
MES, 6Hz, CK = 12-20mmol/kg; side effects = 20mmol/kg). Anti-seizure effects of CA8 and CA10
were considered marginal, even at doses that were poorly tolerated. In contrast two synthetic
derivatives of CA8, 4-EOA and 4-BCCA, showed robust efficacy in the 6Hz, MES, scPTZ models
and reduced side effect liability (e.g. 4-EOA ED50 = 1-1.5mmol/kg).
These studies support the use of certain synthetic MCFA derivatives as an advance on the MCT
KG diet for the treatment of refractory epilepsy and possibly pain and inflammation disorders.
(1) InterVivo Solutions - Canada | (2) CanCog Technologies - Canada | (3) Ketogen Pharma - Canada |
(4) Vibrant Pharma - Canada
Higgins Guy A. | [email protected]
GAD67 IMMUNOREACTIVITY IN THE CENTRAL AMYGDALA AS A MARKER OF
LONG-LASTING CHANGES IN NEURONAL ACTIVITY CAUSED BY ADOLESCENT
PRE-EXPOSURE TO DRUGS OF ABUSE
Sil, Annesha (1) | Pisanu, Augusta (2) | Lecca, Daniele (1) | Scifo, Andrea (1) | Cadoni, Cristina
(2) | Di Chiara, Gaetano (1,2)
Numerous studies suggest that early exposure to drugs of abuse can induce long-lasting
neurochemical and behavioural adaptations in adulthood. Lewis(LEW) and Fisher(F344) rats have
been widely used to study these adaptations, given their different vulnerabilities to drug addiction.
Previous studies have implicated the expression of GAD67(glutamate acid decarboxylase-67) mRNA
in the central nucleus of the amygdala(CeA) as a marker for some of these changes, i.e.
behavioural sensitization. Using fluorescent immunohistochemical techniques, we tested the
validity of GAD67 as a neuronal marker of these changes in the aforementioned strains in the CeA.
Mid-adolescent rats underwent repeated, dose-escalated exposure to either morphine, heroin or
THC(tetrahydrocannabinol) and their effects were determined in adulthood. Pre-exposure to
morphine/heroin decreased GAD67-immunoreactivity(GAD67-IR) in F344 but not in LEW rats, while
THC pre-exposure did not produce any significant change of GAD67 in both strains.
In a second experimental setting, adolescent THC pre-exposure was followed by heroin selfadministration, extinction training and reinstatement by heroin, in adulthood. After 3-4 days of
reinstatement, significant increase in GAD67-IR was observed in THC-pretreated F344 rats but not
in their controls, while no change was observed in the LEW strain.
Since in both experimental settings F344 rats are behaviourally sensitized to opiates, but not to
THC, the results obtained suggest that an increased GAD67 expression cannot be considered a
marker of behavioral sensitization since both a decrease and an increase was observed under two
different experimental settings. On the other hand, LEW rats did not show either behavioural
sensitization to opiates or significant changes in GAD67 in spite of long-lasting changes in reward
and emotional function.
Given that the observed GAD67 changes are not univocally predictive of long-lasting changes in
adulthood, we suggest that differences between strains are due to opposite HPA system
responsivity. Since LEW is the strain more affected by THC pre-exposure, in terms of changes in
reward and emotional function, it might be hypothesized that the observed increase of GAD67 in
F344 strain is a counter-adaptive mechanism protecting against progression toward drug addiction.
(1) Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of
Cagliari, Italy | (2)Institute of Neuroscience, National Research Council of Italy, Italy
Email: [email protected]; [email protected]; [email protected]; [email protected];
[email protected];[email protected]
Sil Annesha | [email protected]
CEREBELLO-CEREBRAL FUNCTIONAL CONNECTIVITY AND SOCIAL
BEHAVIOR IN PATIENTS WITH AUTISM SPECTRUM DISORDERS
Olivito, Giusy (1,2) | Clausi, Silvia (1,2) | Laghi, Fiorenzo (3) | Tedesco, Anna Maria (1,2) |
Baiocco, Roberto (3) | Mastropasqua, Chiara (4) | Molinari, Marco (5) | Cercignani, Mara
(4,6) | Bozzali, Marco (4) | Leggio, Maria (1,2)
Autism spectrum disorders (ASDs) are neurodevelopmental disorders mainly characterized by
core deficits in social communication and stereotyped patterns of behavior. It has been
proposed that ASDs' deficits can be explained by an impairment of "Theory of Mind" (ToM)
processes. ToM refers to the ability of attributing mental states to self and other in order to
predict and explain complex behaviors. The cortical underconnectivity theory has been
proposed as an explanatory model for ASDs suggesting that an abnormal functional connectivity
among cortical and subcortical brain areas may be responsible for ASDs’ social deficits. Since
the cerebellum has also been suggested to be part of the distributed neural circuits that may
be dysfunctional in ASDs, in the present study we investigated the resting-state functional
connectivity (FC) between the cerebellar Dentate Nucleus (DN), the main cerebellar output
channel, and the cerebro-cortical targets, in order to assess Dentate-Cerebral FC changes that
might account for social deficits in ASDs patients. We compared 9 adults with ASDs and 36
typically developing subjects. Patients were administered with an extensive social cognition
battery. Functional Magnetic Resonance Imaging (fMRI) scans were acquired for all participants
and the mean time course was extracted separately for left and right DN to explore differences
in connectivity between groups. Altered FC was found to affect cerebral regions of the social
brain networks (i.e. Default Mode network) in patients compared to controls. Interestingly, a
correlation was found between altered FC and social cognition scores in ASDs. In conclusion the
present data provide the first evidence that DN FC is altered in ASDs patients and suggest that
the cerebellum might play a crucial role in determining social behavior features of ASDs via
interaction with key cortical social brain regions, such as Default Mode structures.
(1) Ataxia Lab - IRCCS - Rome IT | (2) Psichology - Univ Sapienza - Rome IT | (3) Develop./Social
Psychology - Univ Sapienza - Rome IT | (4) Neuroimaging Lab - IRCCS - Rome IT | (5) Neurological IRCCS - Rome IT | (6) Clinical Imaging Sciences Centre (CISC) - University of Sussex - Brighton UK
[email protected] | [email protected] | |
Olivito Giusy | [email protected]
DISTRIBUTION AND CONNECTIVITY OF VIP+ INTERNEURONS IN THE
BASOLATERAL COMPLEX OF THE MOUSE AMYGDALA
Paradiso, Enrica (1) | Xu, Chun (2) | Rhomberg, Thomas (1) | Kremser, Christian (3) | Lüthi,
Andreas (2) | Ferraguti, Francesco (1)
Interneurons in the basolateral amygdala (BLA) are a heterogeneous group of neurons that
regulate principal cell activity. Among them vasoactive intestinal polypeptide (VIP) expressing
interneurons are believed to preferentially target other types of interneurons leading to the
disinhibition of principal cells. Nevertheless, little is known about VIP+ interneurons in BLA and
their contribution to amygdala microcircuits. Our aim is to elucidate their distribution in
different subdivision of the BLA, characterize their neurochemical properties, and define their
pre- and post-synaptic partners.
Immunohistochemical analyses revealed that the posterior subdivision of the basal nucleus
(BLp) contains the highest density of VIP+ neurons (1347 cells/mm3). In contrast, the
dorsolateral subdivision of the lateral nucleus (LaDL) display the lowest density (769 cells/mm3).
The highest rate of colocalization between VIP+ and the calcium binding protein calretinin (CR)
was found in the LaVM (68.04 %) followed by the LaDL (55.29%) while in BLa and BLp half of the
VIP+ neurons coexpressed CR.
To elucidate VIP+ interneurons presynaptic afferents, we take advantage of the mono-transsynaptic retrograde tracing technique using the glycoprotein deleted EnvA pseudotyped rabies
virus (RV) EnvA-SADΔG. The stereotactic injection in VIP-Cre mice BLA of Cre-dependent AAV
vectors carrying the EnvA receptor and the native RV glycoprotein followed by EnvA-SADΔGEGFP injection, restricts the entry of the RV in VIP+ cells and limits his retrograde transport to
first order presynaptic neurons.
Even though the majority of retrogradely labeled neurons were detected in the BLA,
presynaptic partners of BLA VIP+ interneurons are widespread throughout the telencephalon in
areas implicated in the processing of sensory stimuli related to fear memories and in several
thalamic and hypothalamic areas of the reward-emotional circuitry.
Our data indicate that BLA VIP+ interneurons might belong to more than one class of
interneurons, receiving short and long range inputs from areas involved in amygdala-dependent
behaviors.
(1) Department of Pharmacology - Medical University Innsbruck - Austria | (2) Friedrich Miescher
Institute for Biomedical Research - Basel - Switzerland | (3) Department of Radiology - Medical
University of Innsbruck - Austria
Paradiso Enrica | [email protected]
EFFECT OF EIGHT FATTY ACIDS CONTAINED IN HUMAN AMNIOTIC FLUID
ON ANXIETY-LIKE BEHAVIOR IN THE WISTAR RAT
Rodríguez-Landa, Juan, F (1) | Contreras, Carlos, M (2) | Guillen-Ruiz, Gabriel (1) | GarcíaRíos, Rosa, I (1) | Cueto-Escobedo, Jonathan (1) | Bernal-Morales, Blandina (1)
Human amniotic fluid produces anxiolytic-like effects in rats evaluated in both elevated plus
maze and burying defensive tests, which is associated with the presence of eight fatty acids
constantly identified in the amniotic fluid. In fact, a mixture elaborated with the same eight
fatty acids found in amniotic fluid (linoleic, palmitic, stearic, myristic, elaidic, lauric, oleic,
and palmitoleic acids) produces anxiolytic-like effects similar to diazepam in adult Wistar rats;
however, the effect of each fatty acid administered individually on anxiety-like behavior
remains to be explored. In a first experiment, in Wistar rats we evaluated the separated action
of each fatty acid (linoleic, 44; palmitoleic, 71; stearic, 37; myristic, 30; elaidic, 15; lauric, 4;
oleic, 80; and palmitic, 153 μg/rat, s.c.) resembling the concentration found previously in
human amniotic. Individual effects were compared with a vehicle (propylene glycol 96% and
ethanol 4%), and a reference anxiolytic drug (diazepam, 2 mg/kg). In a second experiment,
several concentrations of the effective fatty acid to produces anxiolytic-like effects (i.e.
myristic acid, identified in the first experiment) were also evaluated in the same behavioral
tests. Only myristic acid and diazepam significantly increased the time spent in the open arms
and reduced the anxiety index compared with vehicle in the elevated plus maze, without
significant changes in general locomotor activity. The myristic acid only produces anxiolyticlike effects in a similar concentration identified in human amniotic fluid (3 mg), but not with
lower or higher concentrations. In conclusion, from the eight fatty acids constantly identified
in human amniotic fluid reported with anxiolytic-like activity, only myristic acid in the same
concentration reported in the amniotic fluid produces anxiolytic-like effects in the Wistar rat.
Partially supported by: CONACyT: CB-2006-1, 61741, and Programa de Fortalecimiento
Académico del Posgrado de Alta Calidad I010/458/2013, C-703/2013.
(1) Universidad Veracruzana - Mexico | (2) Universidad Nacional Autónoma de México - Mexico
Rodríguez-Landa Juan F | [email protected]
CONDITIONAL MUTANT OF BASSOON IN EXCITATORY FOREBRAIN
SYNAPSES DISTURBS DENTATE GYRUS STRUCTURE AND FUNCTION
Annamneedi, Anil (1) | Caliskan, Gürsel (2) | Fejtová, Anna (1) | Gundelfinger, Eckart, D (1)
| Stork, Oliver (2)
Bassoon, a large scaffolding protein, is one of the core components of the cytomatrix at the
active zone (CAZ) of presynapses. Previous studies showed its involvement in regulated
neurotransmitter release with altered vesicle reloading and the regulation of P/Q-type Calcium
channels. Mice with constitutive ablation of the Bassoon gene show disturbances of pre-synaptic
functions and develop epileptic seizures. In order to address specific behaviorally relevant
synaptic functions of Bassoon, we have generated conditional mutants with loxP sites flanking
exon2 of the Bassoon gene. Activation with Emx1-CRE driver mice allowed for a specific
inactivation of Bassoon in forebrain excitatory neurons (cKO mice) as confirmed by
immunohistochemical staining. cKO mice display an increase in background context fear
memory, but normal foreground context and unaltered auditory cued fear memory, when
compared to controls. Moreover, cKO mice show improved performance in a pattern separation
paradigm using object displacement in an open field. Object recognition memory per se,
however, is not significantly affected. These behavioral changes point towards a functional
disturbance of the dorsal dentate gyrus in cKO mice. Indeed, electrophysiological analysis
revealed that cKO mice show increased baseline transmission in the medial perforant pathway
suggesting increased excitability of dentate gyrus (DG) granule cells upon stimulation of
perforant path. In line, Golgi impregnation of DG granule cells unveils an increased apical
dendrite length, with increased complexity in cKO mice. Earlier it was shown that, constitutive
knockout of Bassoon have increased levels of BDNF in hippocampus, cortex and striatum and
the effect of BDNF overexpression has been reported to alter the dendritic complexity in DG.
Current studies are designed to measure the levels of BDNF in subdivisions of hippocampus of
cKO mice. Further we will dissect the mechanism underlying the interaction of Bassoon and
BDNF in different brain regions and their consequence for animal behavior.
(1) Leibniz Institute for Neurobiology (LIN) - Magdeburg - Germany | (2) Department of Genetics and
Molecular Neurobiology - OvGUniversity Magdeburg - Germany
Annamneedi Anil | [email protected]
DIFFERENTIAL OUTCOMES AND VISUAL WORKING MEMORY IN PATIENTS
WITH ALZHEIMER´S DISEASE
Estévez, Angeles, F (1) | Roldán-Tapia, Dolores (1) | Ruiz de la Fuente, Marina (2) |
Carmona, Isabel (1) | Torrecillas, Eva (2)
The differential outcomes procedure (DOP) refers to the increase in performance and terminal
accuracy seen in conditional discrimination tasks when each of the stimuli-response associations
to be learned is followed by a unique outcome. In addition to the benefits of the DOP observed
with conditional discrimination learning, there is an increasing amount of evidence suggesting
positive effects with memory tasks as well (see López-Crespo & Estévez, 2013, for a review).
In the present study we aimed to explore whether this procedure would also improve visual
recognition memory in patients with Alzheimer’s disease. The results obtained, along with
those from previous studies, suggest that this procedure can be an effective technique to
facilitate working memory-based performance especially in those people with memory
impairments.
This research was supported by grant PSI2012-39228 from Spanish Ministerio de Economía y
Competitividad.
(1) Universidad de Almería - Spain | (2) CEDAEN - Spain
Roman-Lopez, P | [email protected]
NEUROBEHAVIORAL ALTERATIONS IN A GENETIC MURINE MODEL OF
FEINGOLD SYNDROME 2
Coassin, Alessandra (1) | Fiori, Elena (1) | Babicola, Lucy (2) | Andolina, Diego (2) | Pascucci,
Tiziana (2) | Patella, Loris (2) | Han, Yoon-Chi (3) | Ventura, Andrea (3) | Ventura, Rossella
(1)
Feingold Syndrome (FS) is an autosomal dominant disorder characterized by microcephaly, short
stature, digital anomalies, esophageal/duodenal atresia, facial dysmorphism, and various
learning disabilities. Heterozygous deletion of the miR-17~92 cluster is responsible for a subset
of FS (Feingold syndrome type 2, FS2), and the developmental abnormalities that characterize
this disorder are partially recapitulated in mice harboring a heterozygous deletion of this cluster
(miR-17~92~/+ mice). Although Feingold patients develop a wide array of learning disabilities,
no scientific description of learning/cognitive disabilities, intellectual deficiency, and brain
alterations have been described in humans and animal models of FS2.
In this study, we examined the behavioral profiles of infant and adult miR-17~92∆/+ mice. We
monitored the development of physical landmarks, reflex, ultrasonic vocalizations and
locomotor activity in pups. Moreover, motor, cognitive, spatial, memory and emotional deficits
were investigated in adult miR-17~92∆/+ mice. We also analyzed dopamine (DA),
norepinephrine (NE) and serotonin (5-HT) tissue levels in the medial prefrontal cortex (mpFC)
and Hippocampus (Hip), brain areas involved in executive functions and in memory span.
A decrease in body weight and length and a reduction of the number and duration of
vocalization during the weaning was observed in miR-17~92∆/+ pups. Moreover, deficit in
spatial ability, social novelty recognition and memory span, measured respectively by the
spatial novelty test, social novelty test and Dot-Iot test was evident in adult mice. Finally, we
found lower DA as well as 5HT transmission in the mpFC and Hip, thus suggesting a possible link
between selective cognitive deficits and altered neurotransmission involved in executive
functions. Our data suggest that miR-17~92∆/+ mice have difficulties in processing spatial
information, probably due to a loss of behavioral flexibility, attentional set-shifting and
reduced memory span.
This inclination could be reflect the inability to develop a flexible acting pattern in response
to changing environmental conditions.
(1) Department of Psychology and Center Daniel Bovet Sapienza - University of Rome - Italy | (2)
Santa Lucia Foundation - Rome - Italy | (3) Memorial Sloan-Kettering Cancer Center - Cancer Biology
& Genetics Program - New York - USA
Coassin Alessandra | [email protected]
EFFECTS OF NICOTINE ADMINISTRATION VIA SMOKELESS TOBACCO (SNUS)
ON IOWA GAMBLING TASK IN MEN
Zandonai, Thomas (1) | Mancabelli, Alberto (2) | Falconieri, Danilo (3) | Diana, Marco (4) |
Chiamulera, Cristiano (1)
Introduction: Increasing use among winter athletes of nicotine via smokeless tobacco (snus) has
been explained as a sought cognitive enhancement. The aim of this research was to assess snus
effects on cognitive-task in non-smokers and in daily users.
Methods: Study 1. The aim of this study was to measure the effect of snus administration on
Iowa Gambling Task (IGT), a decision-making processing task. We recruited 40 male nonsmokers. Subjects were randomized to blindly receive snus or placebo on two different days
according to a cross-over design.
Study 2. In this study we investigated the effect of snus on IGT in daily snus users. We recruited
15 male daily snus users who were tested under satiety or 12-hour abstinence condition
following study randomization.
Blood samples were drawn for the determination of nicotine and cotinine levels before and
after snus administration. The Profile of Mood of State questionnaire (POMS) was administered
before and at the end of IGT in both studies.
Results: Study 1. A significant difference was observed for net scores in T1 (first 1-20 choices)
between the snus vs. placebo condition (paired Student’s t-test). Twenty-three subjects
reported adverse events at the end of SS session. No differences were observed in overall net
score (snus vs. placebo).
Study 2. Subjects reported a 5.3 score in Fagerstrom test (FTND-ST). NO significant differences
were observed in overall net score (Abstinence vs. Satiety). Our data showed a significant
difference for net scores in T1 (first 1-20 choices) between two conditions (paired Student’s ttest).
Conclusion: The study shows that snus may produce an early but transient cognitive
improvement on IGT in non-smokers and in snus users. Adverse snus reactions could have
detrimental effects on performance in naïve users. In conclusion, a snus effect on IGT suggests
a transient cognitive potentiation.
(1) Neuropsychopharmacology Lab - University of Verona - Italy | (2) School of Sport and Exercise
Science - University of Verona - Italy | (3) University of Cagliari - Italy | (4) Dept of Chemistry &
Pharmacy - University of Sassari - Italy
Zandonai Thomas | [email protected]
MAPPING REGIONAL BRAIN ACTIVITY DURING TWO-WAY ACTIVE
AVOIDANCE (TWA) BEHAVIOR USING IN VIVO SPECT-IMAGING IN FREELY
BEHAVING RATS
Mannewitz, Anja (1) | Goldschmidt, Jürgen (2) | Bock, Jörg (1) | Braun, Katharina (1)
Feedback learning is essential to adapt a changing environment and to optimize behavioral
interactions in humans and many other mammals. Surprisingly little is known about the brain
circuits, which are involved. Thus, the aim of this study was to identify brain regions, which
are involved in two-way active avoidance (TWA) learning, an established animal paradigm for
feedback learning. SPECT-imaging of regional cerebral blood flow allows monitoring patterns
of neuronal activity repeatedly during different stages of TWA learning. This method provides
a refined temporal image resolution and repeated measurements, and thereby allows
comparing brain activity during different conditions within one individual. Adult female rats
were catheterized via the external jugular vein and injected with the radioactive blood flow
tracer 99m-technetium HMPAO at different time points: a) control: habituation phase (sitting
in the shuttle box without stimuli), b) acquisition (1st training session) and c) memory retrieval
(5th training session). Marked differences in activity were observed between acquisition and
retrieval: during acquisition higher prefrontal cortex activity (prelimbic and cingulate cortex)
and lateral septum were observed in relation to retrieval phase; whereas during retrieval more
subcortical brain regions were activated compared to acquisition, including the subcortical
auditory nuclei (medial geniculate, inferior colliculus), limbic areas (amygdala, nucleus
accumbens) and limbic output system (hypothalamus). In addition, differences between
acquisition and retrieval were observed in the hippocampal formation: during acquisition
asymmetric activity was observed in the dorsal hippocampus, whereas during retrieval activity
was more pronounced in the ventral hippocampus. During both, acquisition and retrieval we
observed higher activity in the auditory cortex compared to the habituation phase. In conclusion,
prefrontal activity during acquisition indicates an involvement of working memory and the
formation of a goal-directed behavioral strategy. Furthermore, the higher activation of limbic
areas such as the ventral hippocampus, amygdala and hypothalamus during retrieval most likely
reflects autonomic and behavioral responses to aversive stimuli.
(1) Univ Magdeburg - Germany | (2) LIN Magdeburg - Germany
[email protected]
Mannewitz Anja | [email protected]
SPATIAL WORKING MEMORY DEFICITS IN AGING: IS IT THAT BAD?
Klencklen, Giuliana (1) | Banta Lavenex, Pamela (1) | Brandner, Catherine (1) | Lavenex,
Pierre (1)
Working memory, the system that keeps limited amounts of information for brief periods of
time to guide behavior, is vulnerable to normal aging. However, spatial working memory,
essential in daily activities such as learning new routes or driving a car, is thought to be
particularly affected in normal aging. Here, we performed an experiment to test the specificity
of this purported age-related decline in spatial working memory, in a real-world allocentric
spatial memory task. We tested 24 healthy elderly (65-75 yrs) and 24 young adults (20-30 yrs)
in an open-field memory task under different conditions designed to compare four types of
memories (spatial working memory, color working memory, spatial reference memory, color
reference memory), under different memory loads (one, two or three items to remember). We
used two distinct measures to characterize memory performance: the number of correct
choices before erring, an estimate of memory capacity; and the number of errorless trials, an
estimate of perfect memory. We found: (1) a general decline of memory performance with age,
(2) a greater deficit in working memory than reference memory, independently of the type of
information, (3), a greater deficit of spatial reference memory than color reference memory,
but (4) no evidence that spatial working memory was more affected than color working memory.
These results suggest that different types of memory are differentially affected in aging, but
that the deficits in memory performance are linked to the representational demands of the
task and not to the type of information to be remembered.
(1) Laboratory for Experimental Research on Behavior - Institute of Psychology - University of
Lausanne - Switzerland
Klencklen Giuliana | [email protected]
SYNAPTIC PLASTICITY ALTERATIONS IN THE CORTICO-ACCUMBENS
CIRCUIT OF HEROIN SELF-ADMINISTERED RESIDENT AND NONRESIDENT
RATS
Stendardo, Emiliana (1) | Avvisati, Riccardo (1) | Meringolo, Maria (1) | Merinelli, Silvia (2) |
Badiani, Aldo (1,3)
We have previously reported the setting of drug self-administration has a powerful influence
on drug intake(Caprioli et al. 2008). Rats that lived in the self-administration (SA) chamber
(ResidentRats) tended to self-administer more heroin than rats that were exposed to the SA
chamber only during testing (NonResidentRats living in a distinct home cage). Also the
neurobiological effects of heroin are a function of setting. In situ hybridization and
immunohistochemistry experiments have shown that the effects of heroin on the expression of
FosmRNA and Fos in the reward regions of the brain are very different in Resident vs.
NonResidentRats (Paolone et al. 2007; Celentano et al. 2009). Fos is a transcription factor that
is thought to be implicated in the early stages of drug-induced neuroplasticity. Thus, we
hypothesized that the setting may influence heroin-induced long term plasticity.In the present
study, we used ex vivo electrophysiological recordings to investigate the effects of heroin SA
on long term cortico-accumbens synaptic plasticity as a function of setting. Both Resident and
NonResident rats were trained to self-administer heroin (25μg/kg/infusion) for 10sessions (3h
each).After 14 days of abstinence from heroin the rats were killed and their brains excised to
obtain parasagittal slices for field recordings. We found that after tetanic stimulation, LTP was
greater in NonResidentRats (fEPSP amplitude about 160% of baseline) than in ResidentRats
(140% of baseline). This suggests that cortico-accumbens (presumably inhibitory) inputs are
reduced when the rats self-administer heroin in their home environment relative to a non-home
setting and may explain why ResidentRats tend self-administer more heroin than
NonResidentRats.
(1) Department of Physiology and Pharmacology-Sapienza University of Rome-Rome-Italy | (2) EBRIRome-Italy | (3) School of Psychology-University of Sussex-Brighton-UK
Stendardo Emiliana | [email protected]
TEST OF NOVELTY REACTIONS IN PRIMATES: NEOPHOBIA OR NEOPHILIA?
Englerova, Katerina (1,3) | Rejlova, Marketa (1,2) | Skalnikova, Petra (1,2) | Rokyta, Richard
(3) | Nekovarova, Tereza (1,2,3)
The ability to distinguish between novel, unknown and familiar objects may be crucial for
successful surviving (i.g. recognition of palatable food or potential predators). Aversion against
anything unknown – neophobia – is evolutionary convenient, but it cannot be strong enough to
prevent from exploring new. Neophobia and neophilia (as a preference for novelty) are
independent of each other and we can imagine them as two vertical axes. Different animal
species exhibit varying degrees of these characteristics, which may be influenced by ecology
and ethology of species, but also by age or sex of individuals and also by type of object or test
situation.
Up to date the most frequently used methods are food-preference experiments or ethological
observations of free, time-unlimited behaviour toward new objects. In our experiment we study
reactions of rhesus monkeys in conditions of time-limited experiment.
Our experiment was designed as a modification of a one-choice test. Two pieces of food of the
same quality and quantity were hidden into two different cups. First was already known; the
second one represented the novel object. This pair of objects was presented to the monkey for
12 times in one session. In the following session, previous novel object was presented as the
„old one“ and a very new object was added. In the second part we tested the objects in the
reverse order to reveal, whether there is a preference for specific objects or not.
Preliminary results show quite a strong consistency in choosing specific objects and also slight
neophobic tendency in time-limited experiment. This finding differs from the results of many
observation experiments and will be discussed.
This project was supported by the GAUK 1508414, by Project Prvouk P34 and by the project
„National Institute of Mental Health (NIMH-CZ)“ - grant number ED2.1.00/03.0078 of the ERDF.
(1) National Institute of Mental Health, Klecany, Czech Republic
(2) Ecology and Ethology Research Group, Department of Zoology, Faculty of Natural Science, Charles
University in Prague, Prague, Czech Republic
(3) Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
Englerova Katerina | [email protected]
CROSS-STRUCTURAL INTERACTION BETWEEN THE HIPPOCAMPUS AND
THE VENTRAL STRIATUM IN SPATIAL MEMORY
Torromino, Giulia (1,2) | Biasini, Giorgia, M. (1,2) | Autore, Livia (1,2) | Middei, Silvia (2) |
Oliverio, Alberto (1,2) | Mele, Andrea (1,2)
Well established is the role of the hippocampal complex (HPC) in the processing of spatial
information. However, it is increasingly clear that long-term storage of complex information
requires the parallel participation of multiple brain regions. The ventral striatum (VS) has been
recently associated to spatial learning and memory processes. Based on the existence of dense
ipsilateral projections that connect the HPC to the VS through the ventral subiculum (vSub),
we asked if a cross talk between the vSub and the VS could be necessary for memory formation.
To test this hypothesis, we performed a pharmacological asymmetric disconnection between
the vSub and the VS to block the transmission within each pathway in each hemisphere. Based
on our previous results, we administered the NMDA receptor antagonist AP-5 (0.15 μg/side) in
the vSub and the contralateral VS immediately post-training in mice trained in a massed version
of the Morris water maze. This procedure impaired the mice ability to locate the platform on a
probe trial 24 hrs after training.
Our results suggest that a cross talk between the vSub and the VS regions is necessary for
memory consolidation and that this communication is NMDAR-dependent. Further experiments
are ongoing to understand whether inter-structural communication is needed for experiencedependent plasticity to occur within the VS.
(1) Department of Biology and Biotechnology "Charles Darwin" and Centre for Research in Neurobiology
"Daniel Bovet" - Sapienza University of Rome - Rome Italy | (2) CNR-IBCN - Cellular Biology and
Neurobiology Institute - Rome Italy
Torromino Giulia | [email protected]
CHRONIC VOLUNTARY WHEEL-RUNNING EXERCISE MODULATES THE
REWARDING EFFICACY AND THE LOCOMOTOR RESPONSES OF Δ9TETRAHYDROCANNABINOL
Katsidoni, Vicky (1) | Panagis, George (1)
Physical exercise induces several psychophysical effects and affects neurotransmission,
including endocannabinoids, which may modulate the rewarding responses to addictive drugs
and affect drug-taking behavior. The aim of the present study was to examine the effects of
chronic voluntary wheel-running exercise on the rewarding and locomotor-stimulating effects
of Δ9-tetrahydrocannabinol (Δ9-THC) using the intracranial self-stimulation (ICSS) procedure
and the open field test (OFT).
Male Sprague-Dawley rats were randomly divided in two groups: exercised (voluntary wheelrunning from weaning -day21- until early adulthood) and non-exercised rats. For the ICSS
procedure, at the age of three months the rats were implanted with a monopolar electrode
within the MFB. After the stabilization of the ICSS behavior, the animals of both groups received
systemic injections of Δ9-THC (0, 0.1, 0.5 and 1mg/kg, i.p.). Each test consisted of a pre-drug
and a post-drug rate-frequency function determination. For the OFT, the animals received
systemic injections of Δ9-THC (0, 0.1, 0.5 and 1mg/kg, i.p.) and their locomotor activity was
measured for 3 hours. Wheel-running exercise decreased the reward-facilitating effect of the
lowest dose of Δ9-THC, while it increased the anhedonic effect produced by the highest dose.
Moreover, the hyperlocomotion induced by the low doses of Δ9-THC and the hypolocomotion
induced by the highest dose of Δ9-THC was blocked in the exercised rats compared to the
control group. Altogether the present results reveal that long-term voluntary exercise can have
“protective effects” against drug-seeking behavior and drug addiction, possibly by reducing the
reward-facilitating and psychomotor-stimulating effects of Δ9-THC
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(1) University of Crete - Department of Psychology - Laboratory of Behavioral Neuroscience - 74100
Rethymno - Crete - Greece
Panagis, George | [email protected]
SLEEP ENHANCES CONSOLIDATION OF SOCIAL MEMORY IN RATS
Sawangjit, Anuck (1) | Kelemen, Eduard (1) | Born, Jan (1) | Inostroza, Marion (1)
Recognition of conspecifics is an important cognitive ability in social species like humans and
rats. Social memory is processed in the hippocampus. While studies showed beneficial effects
of sleep in consolidating various types of hippocampus-dependent memories (i.e., spatial and
contextual information), no sleep impact on social memory has been reported. Here we aim to
study effect of sleep on consolidation of information about conspecifics. Social discrimination
task was performed in a modified 4-arm radial maze. During three 10-min sampling sessions 8week old Long-Evans rats were allowed to explore a 3-week old juvenile rat of the same strain
which was presented at a different location (arm) of the maze during each sampling session.
The three sampling sessions were followed by a 90 minute retention period of sleep or sleepdeprivation (SD). During a 10-min test phase the familiar juvenile rat from the sampling sessions
was presented along with a novel juvenile rat - each rat in an opposite arm of the maze. Social
memory was measured by the percentage of time sniffing the novel juvenile. The sleep group
had a stronger preference for the novel juvenile than SD group during the first minute of the
test session and could detect animal novelty faster than SD group. The strong preference for
exploration of the novel juvenile rat in the sleep group was also confirmed in analysis that
accounted for known effects of sleep on spatial/temporal memories. Our results demonstrate
enhancing effect of sleep on consolidation of social memory.
(1) Institute of Medical Psychology and Behavioral Neurobiology - University of Tübingen - Germany
Sawangjit Anuck | [email protected]
EXPOSURE TO A MILDLY ADVERSIVE EARLY EXPERIENCE AFFECTS ADULT
BRAIN SEROTONERGIC SYSTEM AND THE EMERGENCE OF A DEPRESSIVELIKE PHENOTYPE IN RATS
Kalpachidou, Theodora (1) | Diamantopoulou, Anastasia (1) | Aspiotis, Georgios (1) |
Gampierakis, Ioannis, A. (1) | Stylianopoulou, Fotini (1) | Stamatakis, Antonios (1)
Depression is a major neuropsychiatric disorder and adverse early life experiences have been
implicated in its etiopathogenesis. In the present work we employed a neonatal experience of
mild adversity, which involves exposure of rat pups during postnatal days 10 to 13 to a T-maze
in which, in spite of approaching the mother, contact with her is denied (DER). Animal models
for depression have been developed which employ the exposure to chronic stress, since it is
known that it elicits depressive-like behaviors. During adulthood DER males were subjected to
a chronic social stress (CSS), consisting of exposure to a resident intruder test for 4 weeks. In
order to monitor the response to the CSS, at the end of each week, sucrose preference and
behavior in the open field were measured. At the end of the fourth week, in addition to the
above parameters, immobility was measured in the forced swim test. Animals were sacrificed
and levels of serotonin (5-HT) and its type 1A receptor (5-HT1AR) were measured by HPLC and
immunohistochemistry, respectively, in the prefrontal cortex, hippocampus and amygdala.
Interestingly, DER males exhibited anhedonia in the sucrose preference test even before the
exposure to CSS. Control animals progressively developed significant anhedonia during the
exposure to the CSS. In the open field reduced locomotion was observed in all animals after the
first and second week of the CSS but after the third week the control rats appeared to have
adapted, and returned to normal, whereas the DER rats continued to exhibit low levels of
locomotion. In the forced swim test DER rats spent more time floating; they also had lower
levels of serotonin in the hippocampus and 5-HT1AR in different brain areas, further supporting
their depressive-like phenotype.
(1) Biology Biochemistry lab - School of Health Sciences - National and Kapodistrian University of
Athens - Greece
Kalpachidou Theodora | [email protected]
THE ASSIGNMENT OF AFFECTIVE/MOTIVATIONAL VALUE TO SENSORY
STIMULI IS MEDIATED BY THE TE2 CORTEX.
Grosso, Anna (1) | Cambiaghi, Marco (1) | Renna, Annamaria (1) | Milano, Luisella (1) |
Merlo, Giorgio, R (1) | Sacco, Tiziana (1) | Sacchetti, Benedetto (1)
Sensory cues, such as sounds, odors or colors, acquire positive or negative value through their
association with rewards or punishments. Sensory cortex participates to emotional learning and
memory, however its role in emotional associative processes is far to be defined. In the present
work we tested whether the higher order auditory cortex Te2 is involved in the elaboration and
subsequent memorization of the sensory features of conditioned stimuli (CS) and unconditioned
stimuli (US) (perceptual learning), the linking of sensory stimuli (S-S learning), or the
association of a CS with an emotional response.
To face this issue, we used two learning tasks: the sensory preconditioning and the secondorder conditioning paradigms. In sensory preconditioning paradigm, animals were trained to
associate two distinct sensory stimuli (CS1 -CS2 pairing) and then were conditioned to associate
CS1 to an aversive US. In second-order conditioning, animals were first trained to associate CS1
with the aversive US, and then were exposed to CS2-CS1 pairing. Te2 was inactivated shortly
after CS2-CS1 pairing in both paradigms through tetrodotoxin (TTX) administration and memory
retention was tested after 1 month.
In the sensory preconditioning, freezing responses to CS1 (almond odor) were similar between
TTX-treated animals and control groups. When tested with CS2 (tone), both the TTX- and salinetreated animals maintained their strong freezing responses. In the second-order conditioning
paradigm, TTX treatment had a significant amnesic effect towards CS2. Thus, the reversible
inactivation of the Te2 cortex impairs the association between a sound and an affective stimulus
during a second-order paradigm whereas it leaves the association between two neutral tones
intact. In conclusion, Te2 activity is required to form the association between sensory cues and
their affective properties but not for perceptual or S-S learning.
(1) University of Turin - Italy
[email protected]
Grosso Anna | [email protected]
AN EARLY, NON-MOTOR SYMPTOM PARKINSON’S MODEL TO STUDY THE
DOPAMINERGIC REGULATION OF AMYGDALA CIRCUITS IN PATHOLOGICAL
FEAR
Schmuckermair, Claudia (1) | Sara, Ferrazzo (1) | Francesco, Ferraguti (1)
Parkinson’s disease (PD) is classically considered as a movement disorder resulting from the loss
of dopaminergic (DA) neurons in the substantia nigra (SNc) and at least in part of the ventral
tegmental area (VTA). However, considerable evidence suggests that non-motor symptoms,
including pathological fear and anxiety, predate the emergence of motor impairment in PD
patients. Motor symptoms become typically apparent only after 70% loss of nigral DA neurons,
likely due to the large DA receptor reserve of the striatum. On the other hand, psychiatric
symptoms may depend on a lower capacity of the limbic system to adapt to DA denervation
compared to the striatum. However, limbic brain structures are believed to be innervated
predominantly by VTA DAergic cells, which show a lower susceptibility to PD-associated
neuronal death.
We stereotactically delivered varying doses (0.2μg, 0.5μg, 1μg, 2μg, 4μg in 0.2μL respectively)
of the neurotoxin 6-hydroxydopamine (6-OHDA) into the basal amygdala (BA) of C57Bl6/J mice
to selectively lesion midbrain DA neurons innervating the amygdala and presumably also other
structures of the limbic system. Stereological analysis of the two main mesencephalic DA nuclei,
the SNc and VTA, revealed that intra-BA 6-OHDA injections resulted in up to 30% cell loss in the
SNc while the VTA lesion were substantially lower.
DAergic denervation comprised a subset of amygdaloid structures (lateral and basal amygdala,
all intercalated cell populations and the amygdalostriatal transition area), but spared the
central amygdaloid nucleus. Furthermore, DAergic denervation was evident in the ventral
hippocampus whereas other limbic structures like the prefrontal cortex were unaffected.
Our results question the widely accepted fact that the amygdaloid complex is innervated by
mesolimbic projections of the VTA but suggest a substantial participation of SNc DAergic
neurons. Further studies have to clarify the exact origin of DAergic innervation of the
functionally distinct amygdaloid subnuclei.
Supported by FWF SFB-F44
(1) Institute of Pharmacology - Medical University Innsbruck - Austria
Schmuckermair Claudia | [email protected]
LATERAL SEPTUM RESPONDS TO THE FIRST EXPOSURE TO A CONSPECIFIC
IN NAIVE DOMESTIC CHICKS
Mayer, Uwe (1) | Rosa Salva, Orsola (1) | Dorigatti, Sara (1) | Vallortigara, Giorgio (1)
The septal nuclei are an evolutionarily well-conserved part of the limbic system, present in all
vertebrate groups. Functionally the lateral septum is known to be involved in many important
aspects of social behaviour and is usually considered as a key node of the social behavior
network. In the present study we wanted to know if simple exposure to a conspecific for the
first time in a naive animal will selectively activate septal areas. We measured brain activities
by visualizing the immediate early gene product c-Fos with a standard immunohistochemical
procedure. Notably, lateral Septum showed higher activation in subjects exposed to a
conspecific if compared to the control animals which were exposed to an empty chamber in
the same acoustical environment. We also measured activity in the intermediate medial
mesopallium (IMM, an area involved in filial imprinting in chicks). This is, to the best of our
knowledge, the first demonstration of septal involvement in response to the visual appearance
of social partners in visually naive animals. This result indicates that previous visual experience
and specific learning events are not necessary to establish this function, which is present shortly
after birth.
(1) Center for Mind/Brain Sciences - University of Trento - Rovereto - Italy
Mayer Uwe | [email protected]
OPTOGENETIC STIMULATION OF BASAL AMYGDALA TERMINALS IN
NUCLEUS ACCUMBENS SUPPRESSES CUE-EVOKED ALCOHOL SEEKING AND
DRINKING
Millan, Zayra (1) | Janak, Patricia (1)
The nucleus accumbens shell strongly inhibits feeding during satiety, reward seeking in the
presence of an unrewarded cue, and drug seeking following its extinction. Understanding the
mechanisms that promote suppressive control over motivated behavior has important
implications for pathologies such as drug addiction and binge eating disorders, which are
characterized by a significant loss of control over consumption. Here we used an optogenetic
approach to examine basal amygdala (BA) projections that target the accumbens shell
[NAc(shell)] and whether stimulation of these NAc(shell)-projecting BLA terminals might be
sufficient to suppress conditioned behavior evoked by alcohol-predictive cues. Rats received
intermittent homecage access to EtOH (15%v/v) followed by Pavlovian conditioning of a 10s
auditory cue reinforced with delivery of EtOH (15% v/v). On test, rats were assessed for cueevoked seeking in the presence of both non-reinforced and reinforced EtOH cues. We found
that stimulation of BA terminals in AcbSh at the time of the cue impaired conditioned port
entries under non-reinforced or reinforced test conditions. Importantly, when cue-associated
EtOH was delivered at the offset of optical stimulation, rats maintained their ability to port
entry. This latter finding suggests that the suppressing effect of stimulation on conditioned
behavior is well-timed to the duration of stimulation. Finally, we examined whether the
inhibitory effect of BA-to-NAc(shell) stimulation could also acutely interrupt licking during
bouts of alcohol drinking. Rats were placed on a 10 min homecage access regime prior to
stimulation test. We confirmed the ability of this pathway to suppress drinking behavior.
Together, these findings suggest that optogenetic stimulation of BA-to-NAc(shell) pathway is
sufficient to acutely interrupt conditioned and unconditioned alcohol-motivated behavior.
(1) Johns Hopkins University - USA
Millan Zayra | [email protected]
EVALUATING THREAT INTENSITY: A ROLE FOR THE LATERAL
ORBITOFRONTAL CORTEX
Costanzi, Marco (1) | D'Alessandro, Francesca (1) | Saraulli, Daniele (2) | Cannas, Sara (3) |
Rossi Arnaud, Clelia (4) | Cestari, Vincenzo (5)
Traumatic experiences can generate fearful memory that persists for long time, contributing
to the onset of anxiety-relatad disorders like Post Traumatic Stress Disorder (PTSD). Different
strategies aimed at erasing fear memories have been designed, even though limits about their
efficiency in treating anxiety disorders have been pointed out.
We have recently proposed a new behavioral procedure to down-regulate fear expression in an
animal model of PTSD. In such a procedure, mice conditioned with a shock of high intensity
were treated for five consecutive days with a pain threshold footshock administration (PTtreatment). The PT-treatment is able to (I) prevent spontaneous recovery, (II) prevent fear
reinstatement, (III) reduce fear sensitization, (III) reduce anxiety levels and (IV) reduce social
withdrawal. The results suggest that the efficiency of PT-treatment could be due to a reevaluation of traumatic experience based on shock devaluation.
Given the role of the lateral orbitofrontal cortex (lOFC) in integrating information about the
value of stimuli and in devaluation paradigms, we investigate the role of this brain area in the
re-evaluation of shock intensity. To this aim, we analyze the activity of lOFC (through c-fos
analysis) in conditioned mice submitted to a treatment with PT shock, high shock (the same
level of that used during the training) or without shock.
The results provide support for the role of lOFC in the re-evaluation of the aversive value of
traumatic experience, modifying the representation of US through devaluation like process.
(1) LUMSA and CNR IBCN - Italy | (2) Dept of Psychology - Sapienza University and CNR IBCN - Italy |
(3) CNR IBCN - Italy | (4) Dept of Psychology - Sapienza University - Italy | (5) CRIN and Dept of
Psychology - Sapienza University and CNR IBCN - Italy
D'Alessandro Francesca | [email protected]
LATERAL SEPTUM RESPONDS TO SELF-PROPELLED MOTION IN NAÏVE
DOMESTIC CHICKS
Lorenzi, Elena (1) | Mayer, Uwe (1) | Rosa Salva, Orsola (1) | Vallortigara, Giorgio (1)
The septal nuclei are an evolutionarily well-conserved part of the limbic system, present in all
vertebrate groups. Functionally the lateral septum is known to be involved in many important
aspects of social behaviour and is usually considered as a key node of the social behavior
network. The detection of animate creatures is fundamental for survival and social interaction
in animal species.
Simple shapes moving in a self-propelled fashion (implying the presence of an internal energy
source to the moving object), are spontaneously perceived as animated and engage attention
since infancy. Autonomous changes in speed are one of the cues associated with animacy
perception. We were able to demonstrate that newly hatched visually naïve chicks prefer a
simple object that changes its speed (accelerating and decelerating) to an identical object that
moves at constant speed, suggesting that these mechanisms are predisposed and active at birth.
No studies so far have investigated septal involvement in detection of animacy. To study the
neuronal basis of this phenomenon, we exposed two groups of visually naïve chicks to either
one of the two stimuli and we visualized brain activity by an immunohistochemical staining of
the immediate early gene product c-Fos.
Preliminary results suggest differential involvement between the two groups for the lateral
Septum. We also measured activity in the intermediate medial mesopallium (IMM, an area
involved in filial imprinting in chicks). Notably, lateral Septum showed higher activation in
subjects exposed to speed changes rather than to constant motion, implying the involvement
of this higher order social brain area in processing of visual cues to animacy.
(1) University of Trento - Italy
[email protected]
Lorenzi Elena | [email protected]
MATERNAL IMMUNE ACTIVATION IN MICE: A RE-EXAMINATION OF THE
NEUROBEHAVIOURAL PHENOTYPE IN THE C57 MOUSE STRAIN
Vigli, Daniele | Scattoni, Maria Luisa | Palombelli, Gianmauro | Canese, Rossella | Ricceri,
Laura
Potential environmental risk factors for several neuropsychiatric disorders (e.g. schizophrenia
and autism) include prenatal viral/bacterial infections. Rodent models of maternal immune
activation (MIA) have thus been developed and widely used also in preclinical studies. We
investigated long-term neurobehavioural effects of a maternal viral infection. Polyinosinicpolycytidylic acid (Poly I:C), a synthetic analog of double-stranded RNA to mimic a viral
infection, was injected into pregnant C57BL6/J dams. Exploration in an open field test,
stereotypic marble burying behaviour, sociability in the three-chamber test, fear conditioning
and extinction, pre-pulse inhibition (PPI) were assessed at adulthood in both sexes. Moreover,
in vivo brain magnetic resonance imaging and spectroscopy (MRI and 1H-MRS, 4.7T) were
assessed. Data were analysed always considering the litter-effect. Increased stereotyped
rearing and jumping responses were evident during both open field and marble burying tests.
Lack of the expected habituation profile in adult Poly I:C exposed mice and a less anxious
profile were evident in the open field test. In the three-chamber test, Poly I:C treated male
mice showed an increased sniffing response of the cage containing the familiar stimulus. In the
fear conditioning test extinction impairments were evident: three days after testing Poly I:C
males showed a delay in the initial part of the session, Poly I:C females showed a extinction
delay throughout the test only one week later. PPI results suggest that sensorimotor gating
deficits were evident in Poly I:C exposed mice. As for MRI, Poly I:C female brain volume is
decreased by 5% when compared to control. Prenatal immune activation induces long-term
behavioural alterations primarily in explorative/stereotyped motor domains and behavioural
flexibility, sparing cognitive and social competences. As a whole this experimental model
appears a useful tool to evaluate MIA as a risk factor for brain development, rather than an
animal model of a single neuropsychiatric disorder.
(1) Department Cell Biology and Neuroscience - Istituto Superiore di Sanità - Italy
Ricceri Laura | [email protected]
BRAIN DYNAMICS OF VISUAL AWARENESS IN THE AFFECTED FIELD OF A
HEMIANOPIC PATIENT
Bollini,Alice (1) | Sanchez-Lopez, Javier (1) | Pedersini, Caterina, A (1) | Moro, Sancho (1) |
Savazzi, Silvia (1) | Marzi, Carlo, A (1)
One of the most intriguing topics under scientific investigations are the neural correlates of
visual awareness. One strategy that has been proven fruitful is to study conscious-unconscious
dissociations in brain-damaged patients, as for example hemianopic patients, while they
perform in a visual task. Homonymous Hemianopia, i.e. a loss of part of the visual hemifield
contralateral to a lesion of V1 and/or of the post-chiasmatic visual pathways is considered to
be irreversible, but it has been shown that some form of unconscious visually guided behavior
may still be present. In the present study, we recorded visual event-related potentials (ERPs)
while a hemianopic patient performed an orientation discrimination task with moving or static
square-wave gratings presented in the affected or in the intact hemifield. The behavioral
results showed that the patient had a performance above chance and a conscious feeling of
something appearing in her blind hemifield but without stimulus perception. The ERP analysis
showed a negative component in the N1 domain when the stimulus appeared in the blind
hemifield. Interestingly, this component was present only in the electrodes of the damaged
hemisphere. Further analysis of the frequency spectrum revealed an increase of αsynchronization at the same time of the N1-peak, in the same channels, and together with a
significant increase of the intra-trials coherence in the same time-frequency domain. The
analysis of the contralesional electrodes revealed a similar (but weaker) α modulation in
absence of a significant phase-locking. The α-frequency band oscillations in the occipitoparietal regions are known to be important for top-down modulations, i.e., attention and
especially consciousness. It is also known that N1 emerges from the stimulus evoked-activity
that causes the phase reset of α-oscillations. Thus, the absence of phase resetting in the
contralesional hemisphere could explain the absence of N1 and perhaps the absence of full
stimulus awareness.
(1) Department of Neurological and Movement Sciences - Physiology and Psychology Section University of Verona - Verona Italy
Bollini Alice | [email protected]
NOVEL SEROTONIN TRANSPORTER POLYMORPHISM MODULATES THE
EFFECTS OF ACUTE SEROTONIN MANIPULATION ON THE ANXIETY
RESPONSE
Santangelo, Andrea, M (1,2) | Ito, Mitsuteru (1) | Shiba, Yoshiro (1) | Clarke, Hannah, F (1,2)
| Schut, Evelien, H,S (3) | Cockcroft, Gemma (2) | Ferguson-Smith, Anne, C (4) | Roberts,
Angela, C (1,2)
Polymorphisms in the upstream repeat region of the serotonin transporter gene (SLC6A4) is
associated with individual differences in stress reactivity, vulnerability to affective disorders
and response to pharmacotherapy in humans. It has been shown also that individuals carrying
the vulnerable alleles present neurochemical and structural alterations in brain areas involved
in emotional processing. Using the common marmoset Callithrix jacchus, we have recently
identified sequence polymorphisms in the SLC6A4 that, like in humans, is associated with
individual differences in trait anxiety, measured in marmosets by the emotional response to an
unfamiliar person. Marmosets carrying the low-expressing haplotype AC&C showed high trait
anxiety and reduced 5-HT2Abinding specifically in the right anterior insula, which correlated
negatively with trait anxiety. In contrast, the high-expressing haplotypeCT&This was associated
with low anxiety and high 5-HT2A binding.
Some psychiatric patients experience anxiety during the early stages of pharmacotherapy,
which may be associated with poor outcome. Thus, to study possible relationships between this
pharmacotherapy-induced anxiogenic response and the SLC6A4 polymorphisms, we assessed the
effects of acute pharmacological manipulations of serotonin on emotionality in the human
intruder anxiety test, using a selective serotonin reuptake inhibitor (SSRI) citalopram and a
selective 5-HT2A antagonist M100907.
We identified a genotype-dependent behavioral response to both acute pharmacological
treatments. After administration of either the SSRI or the 5-HT2Aantagonist, AC& C high anxious
marmosets (who also presented reduced insula 5-HT2A binding) displayed a dose-dependent
anxiogenic response. Quite the contrary, CT&T low anxious monkeys showed an opposite,
anxiolytic effect with the SSRI and no effect with the 5-HT2A antagonist.
Our findings provide a novel genetic and behavioral primate model to study the neurobiological
and neuropsychopharmacological mechanisms underlying genetic variation-associated complex
behaviors, with specific implications for the understanding of normal and abnormal serotonin
actions and the development of personalized pharmacological treatments for psychiatric
disorders.
(1) Physiology Development and Neuroscience-University of Cambridge-United Kingdom | (2)
Behavioural and Clinical Neuroscience Institute-Cambridge-United Kingdom | (3) Department of
Cognitive Neuroscience-The Netherlands | (4) Department of Genetics - University of Cambridge UK
Santangelo Andrea M | [email protected]
EXPERIENCE OF STAKES IN A RAT GAMBLING TASK INDUCES SELECTIVE GENE
DOWN-REGULATION IN SEROTONIN AND DOPAMINE SYSTEMS: A POSSIBLE
ROLE FOR EPIGENETIC MECHANISM IN GAMBLING PRONENESS
Zoratto, Francesca (1) | Romano, Emilia (1) | Pascale, Esterina (2) | Maccarrone, Mauro (3) |
Adriani, Walter (1) | D’Addario, Claudio (4) | Laviola, Giovanni (1)
Gambling Disorder (GD) is characterized by excessive gambling despite adverse effects on individual
functioning. To date, in spite of some positive findings, it is difficult to draw any conclusion on the
genetics of GD. Indeed, beyond DNA sequence variation, other regulatory mechanisms (like
epigenetic ones) may explain the role of genes in this addiction. Rats underwent an operant-based
protocol (Probabilistic-Delivery Task) for the evaluation of individual propensity to gamble.
Specifically, rats initially learnt to discriminate and consequently to prefer nose-poking for a large
over a small food reward. At this point, few rats were sacrificed to obtain a baseline profile of gene
expression at both central and peripheral levels. Subsequently, the probability of occurrence of
large-reward delivery decreased progressively to very low levels. Thus, rats were faced with
temptation to nose-poke for a binge reward, whose delivery was omitted the majority of times.
After 3 weeks of testing, rats showing a clear-cut and extreme profile of either gambling proneness
(i.e. sustained preference for large-uncertain reward; "gamblers") or aversion (i.e. marked shift in
preference towards small-certain reward; "non-gamblers") were selected and sacrificed 3 hours
after last session. To assess gene abundances and to quantify gene promoters' DNA methylation, we
used Real-Time RT-PCR and Pyrosequencing respectively. We found, in "gambler" vs. "non-gambler"
rats, a selective down-regulation (compared to baseline) of (i) serotonin transporter in prefrontal
cortex, (ii) tyrosine hydroxylase in ventral striatum, (iii) dopamine transporter in lymphocytes.
Regarding DNA methylation, we observed a consistent increase in one specific CpG site at SERT
gene promoter in prefrontal cortex of "gamblers" rats, whereas no changes were detected in the
promoter regions of the other two genes under investigation. Elucidation of epigenetic changes
occurring during GD progression may pave the way to the development of new therapeutic
strategies through specific modulation of epigenetic factors.
Funding source:
This research was partly supported by the Department of Antidrug Policies c/o Presidency of the Council of
Ministries (Italy), Project ”Gambling” (coordinated by GL and WA as PIs); by the EU-FP7 "PrioMedChild"
ERAnet, Project “NeuroGenMRI” (coordinated by WA as PI for Italy); by the Italian Ministry for University
and Research (Futuro in Ricerca RBFR12DELS 001 to CDA).
(1) Sec. Behavioural Neuroscience - Dept. Cell Biology and Neurosciences - Istituto Superiore di Sanità Rome IT | (2) Dept. Medical Surgical Sciences & Biotechnology - University of Rome 'Sapienza' - Rome IT |
(3) School of Medicine and Center of Integrated Research - Campus Bio-Medico University of Rome - Rome
IT | (4) Faculty of Bioscience and Technology for Food Agriculture and Environment - University of Teramo
- Teramo IT
Zoratto Francesca | [email protected]
DIAZEPAM PREVENTS FORCED SWIM-INDUCED STRESS BEHAVIOR ON OPEN
ARMS AND LOCOMOTOR ACTIVITY TESTS IN INFANT RATS.
Bernal-Morales, Blandina (1) | Contreras, Carlos, M (2) | Guillén-Ruiz, Gabriel (1) | CuetoEscobedo, Jonathan (1) | Rodríguez-Landa, Juan F. (1)
Experimental stressors in laboratory rodents are widely used in behavioral neuroscience of
affective disorders (i.e., electrick foot shock, restraint, social isolation, maternal separation,
sleep deprivation and swimming). Forced swimming at 25ºC is a stressor that produces periods
of immobility which is interpreted as lack of motivation to escape. The time of immobility is
reduced by clinically effective antidepressants. Interestingly, most studies on experimental
anxiety and depression use adult male rodents, although anxiety and depression are frequently
detectable in early age as in human infants and adolescents, which justify the study in young
animals. Therefore, the aim of this report was to explore the effect of the forced swim test as
stressor stimulus on motor and anxiety-like behaviour of weanling rats at 21 days postnatal age.
A dose-response curve revealed 0.5 mg/kg was the anxiolytic dose of diazepam in open arm
test. Forced swim at 21PN significantly reduced the time spent on open arms [H(2) = 22.271, p
<= 0.001] and increased anxiety index [H(2) = 20.150, p <= 0.001], compared to control group,
but these effects were reversed in the group forced to swim injected with diazepam (0.5mg/kg).
A similar result was observed in locomotor activity test where crossing was shorter in the group
forced to swim [H(2) = 17.260, p <= 0.001] as compared to control group and the group treated
with 0.5mg/kg of diazepam submitted to swim. We conclude that the impact of forcedswimming in infants rats at 21PN remains after 24h and produces anxiety-like behavior which
is prevented by a low dose of diazepam.
Aknowledgements: Consejo Nacional de Ciencia y Tecnología, México (CONACyT: Proyecto 1840,
Reg. 249708 ), Cuerpo Académico UVE-CA-25 and Programa de Fortalecimiento Académico del
Posgrado de Alta Calidad I010/152/2014C-133/2014.
(1) Universidad Veracruzana - Mexico | (2) Universidad Nacional Autonoma de Mexico - Mexico
Bernal-Morales Blandina | [email protected]
EARLY ENVIRONMENT AFFECTS RESPONSE TO AVERSIVE AND
REINFORCING STIMULI IN ADULT LIFE DEPENDING ON GENOTYPE
Di Segni, Matteo (1) | Andolina, Diego (2) | D'Amato, Francesca (3) | Luchetti, Alessandra (3)
| Conversi, David (1) | D'Apolito, Lina, I (4) | Babicola, Lucy (5) | Puglisi-Allegra, Stefano (1)
| Pascucci, Tiziana (1) | Ventura, Rossella (1)
Recent evidence suggests that early postnatal life represent a crucial period in shaping the
brain circuits and exposure to critical experiences during this period could lead to long lasting
functional alteration of brain circuits involved in motivated behaviors. Nucleus Accumbens
(NAc) and pre-Frontal Cortex (pFC) constitute a common substrate for processing motivationally
salient stimuli. Therefore, experiences occurring during early postnatal period could have
profound and long-lasting impact on cortico-limbic catecholaminergic function modifying
behavioral and neurochemical response to positive and negative stimuli in adulthood. However,
a vast body of literature indicate that early environmental conditions are not per se sufficient
to induce pathological outcomes in adult life and suggest that the interaction between genetic
factors and early environmental conditions is crucial for induction and/or expression of
psychopatologies later in adulthood. C57BL/6J (C57) and DBA/2J (DBA) are inbred strains of
mouse that markedly differ in stress response, stress-induced depression-like behaviors and
susceptibility to drug of abuse. Moreover these strains are characterized by differences in
accumbal-DAergic and mpFC-monoaminergic functions. Here we evaluated the effects of
exposure to a negative condition (restraint) on mpFC and NAc aminergic release, in adult mice
previously expose to early postnatal manipulation (repeated cross-fostering, RCF) and we
observed significant differences in prefrontal-accumbal catecholaminergic response to stress
between RCF and Control mice depending on genotype. Moreover, a different c-fos expression
in cortical and subcortical regions, paralleling behavioral response to stress exposure
(evaluated by Forced Swimming Test) was evident. Furthermore, we evaluated the response to
positive rewarding stimuli by Sucrose Preference Test and cocaine-induced Conditioned Place
Preference. RCF produced different responses toward natural and pharmacological stimuli
depending on genotype. Our data suggest that early post-natal experiences produces long term
effects affecting differently stress coping behavior, central response to stress and behavioural
response to rewarding stimuli in adult C57 and DBA mice.
(1) Department of Psychology and Centre “Daniel Bovet” - “Sapienza” University of Rome - Foundation
Santa Lucia - European Centre for Brain Research - Italy | (2) Department of Applied and
Biotechnological Clinical Sciences - University of L’Aquila - Foundation Santa Lucia - European Centre
for Brain Research - Italy | (3) Institute of Cell Biology and Neurobiology - National Research Council Foundation Santa Lucia - European Centre for Brain Research - Italy | (4) Department of Biology and
Biotechnologies - “Sapienza” University of Rome - Italy | (5) Department of Human Physiology and
Pharmacology “Vittorio Erspamer” - “Sapienza” University of Rome - Italy
Di Segni Matteo | [email protected]
THE EFFECTS OF ARM FATIGUE ON PERCEIVED DISTANCE
Malatesta, Gianluca (1) | Mussini, Elena (2) | Masotta, Achille (3) | Marzoli, Daniele (3) |
Daini, Roberta (2) | Tommasi, Luca (3)
Introduction. According to the embodied cognition perspective, the body and its action
capabilities can influence the perception of spatial layout, and can be used implicitly as a
perceptual standard with which to evaluate distance and size. Interfering with potential actions
(affordances) evoked by an object seems to affect perception. For example, it was shown that
manipulating the handle orientation of an object, in order to make it more difficult to grasp,
it will appear farther away. Moreover, right-handers perceive tools with handle orientations
conguent with a right-handed grasp as closer than tools with handle orientations conguent with
a left-handed grasp. In the present study we experimentally induced an advantage similar to
that of the dominant hand by manipulating arm fatigue. Specifically, we hypothesized that
straining the right arm would increase the perceived distance of objects with a handle
congruent with a right-handed grasp, and vice versa for left arm straining.
Method. 30 participants (15 males and 15 females) strained their right or left arm and shoulder
by lifting a dumbbell and subsequently estimated the minimum distance needed to grasp a
hammer moving towards them, with handle orientations congruent with a right or left grasp.
Results. Results seem to confirm, at least in part, our hypotesis: after straining the left hand,
participants perceived the hammer with left-oriented handles as located farther away than the
hammer with right-oriented handles, whereas no difference was observed after straining the
right arm.
Conclusions. According to our results, we can speculate that arm fatigue, particularly for the
left arm (probably because in right-handers’ it gets tired more easily), affects the perceived
distance of an object with a congruent handle orientation, modulating both actual and imagined
action capabilities.
(1) Department of Neuroscience Imaging and Clinical Sciences - University of Chieti - Italy | (2)
Department of Psychology - University of Milano-Bicocca - Italy | (3) Dept. of Psychological Health and
Territorial Sciences - University of Chieti - Italy
Malatesta Gianluca | [email protected]
NEURONAL CIRCUITS IN THE CENTRAL AMYGDALA UNDERLYING
EMOTIONAL CONTAGION
Rokosz, Karolina | Adam Hamed | Ewelina Knapska
Human empathy emerges over phylogeny from various behavioral precursors. One of the
simplest is emotional contagion, i.e. sharing emotional states between individuals, which can
be modelled in rodents. In our model of socially transferred fear we showed that a brief social
interaction with a fearful cage mate (demonstrator) promotes aversive learning in an otherwise
naïve rat (observer) and activates the amygdala of the observers, especially its central part
(CeA). To elucidate the role of neuronal circuits in the central amygdala of the observers, we
used two methods of functional mapping: transgenic rats expressing in behaviorally activated
neurons a PSD-95:Venus fusion protein and injected with anterograde tracer and a combination
of retrograde tracing with c-Fos ISH. We have identified several afferent and efferent CeA
projections active during socially transferred fear. We discovered strong activation especially
in the periaqueductal gray (PAG) and dorsal raphe nuclei (DRN), structures receiving dense
projections from the CeA and implicated in fear and anxiety disorders. Moreover, we observed
that most of the activated cells are GABA-ergic neurons. To test whether the activated circuits
are similar for the socially and non-socially induced emotions, we used double immunodetection
for a PSD-95:Venus construct and endogenous c-Fos. About 70% of neurons was activated by
both social interaction with fear conditioned partner and subsequent fear conditioning.
Moreover, using optogenetics, we showed that specific activation of CeA neurons involved in
socially transferred fear results in increased anxiety. These findings suggest that there exists a
group of neurons in the central amygdala that is involved in integrating information about a
threat, activated during socially transferred fear and subsequently recruited by learning of fear
responses. Part of these cells is probably specifically involved in socially induced anxiety.)
Polska | Nencki Institute of Experimental Biology | PAS | Institute of Psychiatry and Neurology |
Medical University of Warsaw
Rokosz Karolina | [email protected]
EFFECTS OF IPSILATERAL AND CONTRALATERAL PEDUNCULOPONTINE
TEGMENTAL NUCLEUS GLUTAMATE INJECTION ON VENTRAL TEGMENTAL
AREA STIMULATION-INDUCED FEEDING
Ptaszek, Kacper (1) | Plucinska, Karolina (1) | Jerzemowska, Grazyna (1)
The ventral tegmental area (VTA) is a key structure of dopaminergic mesolimbic system
involved in reward and motivational processes. Ascending excitatory and inhibitory inputs from
the pedunculopontine tegmental nucleus (PPN) have been shown to regulate the activity of the
VTA, suggesting that reward signaling through the mesolimbic system may be dependent on this
brainstem nucleus.
The present procedure consisted in induction of feeding response by electrical stimulation of
the VTA and subsequent injection of glutamate into the contralateral or ipsilateral PPN
(separate groups) using the latency to feed/stimulation frequency curve shift paradigm. Used
method allows the distinguish between motivational and motor aspects of the tested reaction.
Tukey's post hoc test showed that after contralateral (n=9; contra group) and ipsilateral PPN
(n=11; ipsi group) glutamate injection the percentage feeding threshold change was
insignificant in comparison to the control water injection. In the contra group threshold
increased 15.11% ± 7.85% (P>0.503); in the ipsi group decreased 3.49% ± 4.73% (P>0.960).
Insignificant elevation of the frequency threshold in contra group was accompanied with a
parallel rightward and upward shift of the latency-stimulation frequency curve. The curve
upward was significant (one-way Anova test) at the range of current frequencies sensitive to
motor aspect of tested reaction: from 55.58 Hz to 67.25 Hz (55.58 Hz: F(1,70) = 6.694,
P<=0.012; 61.14 Hz: F(1,70) = 66.75, P<=0.012; 67.25 Hz: F(1,70) = 7.783, P<=0.007). In the ipsi
group leftward shift of the curve was significant only at the stimulation frequency of 67.25 Hz
(F(1,86) = 7.887, P<=0.006).
The results indicate that the PPN and VTA belong to the glutamatergic circuitry responsible for
motor function rather than for motivational aspect of food intake.
Research was financed by the Polish National Science Centre (NCN) conferred on the basis of a
decision number DEC-2013/09/N/NZ4/02195.
(1) Department of Animal and Human Physiology - University of Gdansk - Gdansk - Poland
[email protected]
Ptaszek Kacper | [email protected]
EARLY COGNITIVE DEFICITS IN A MOUSE MODEL OF Aβ TOXICITY IN AN
AUTOMATED LEARNIG TASK
Loos, Maarten (1) | Remmelink, Esther (1) | Lubbers, Bart, R (1) | van Kesteren, Ronald, E
(2) | Verhage, Matthijs (2) | Smit, August, B (2)
Aβ oligomer-induced synaptotoxicity is thought to contribute to cognitive decline in Alzheimer’s
disease (AD). To study Aβ oligomer toxicity in vivo, it is key to develop robust cognitive readouts
in mice that represent the direct toxic effects of oligomers. Here we describe a novel 1-night
discrimination learning task to measure cognitive function in mice in an automated home-cage.
In this task, that runs without any human intervention, mice could obtain all their food by
passing through one of three entrances in a wall placed in front of a reward dispenser. A
systemic injection of low doses of MK-801, a non-competitive antagonist of NMDA receptors
that attenuates LTP, impaired discrimination learning in wild type mice, pharmacologically
validating this novel cognitive task. Next, we observed that transgenic mice overproducing Aβ
oligomers were significantly slower at reaching the learning criterion, not only around the age
at which amyloid plaques start to be visible (26 - 30 weeks of age), but also before plaque
formation at 16 weeks of age. These data indicate that the synaptotoxic effects of Aβ oligomers
might have directly affected discrimination learning in this task. A single acute dose of the
BACE1 inhibitor LY2886721, a rate-limiting enzyme in Aβ production, was used to test the
hypothesis that acute reduction of Aβ oligomers is sufficient to restore the early cognitive
deficit in the APP/PS1 mouse model.
(1) Sylics (Synaptologics BV) - The Netherlands | (2) VU University Amsterdam - The Netherlands
Loos Maarten | [email protected]
HOW PHYSICAL ATTRACTIVENESS AND SEX AFFECT THE EMPATHIC BRAIN
RESPONSES TO PAIN
Kamila Jankowiak-Siuda (1) | Krystyna Rymarczyk (2) | Łukasz Żurawski (2) | Katarzyna.
Jednoróg (2) | Artur Marchewka (3)
Empathy is a process that includes affective sharing and imagining and understanding the
emotions of others. The primary brain structures involved in empathy for physical pain include
the anterior insula (AI), the anterior cingulate cortex (ACC) and specific regions of the medial
prefrontal cortex (MPFC). These empathic brain responses vary depending on modulating
factors such as the intensity of the stimulation, the displayed emotion, situational context or
sex. From the evolutionary perspective, the effect of the sex of the person that one empathizes
with should be mediated by the attractiveness of the model. There is no data on that subject
so far, and that is why it is interesting to investigate how physical attractiveness effect the
level of empathizing. Twenty-seven subjects were studied (14 female and 13 male) using fMRI.
They watched short video-clips, 16 with physically more attractive men and women, 16 with
less attractive men and women, showing experiencing pain and without experiencing pain. The
results have revealed an interaction effect of sex and attractiveness of the models. The ROI
analysis has shown stronger activation in AI and ACC for less attractive men then for attractive
women, and for attractive women then for attractive men. Evolutionary psychology studies
suggest that beauty is valued more highly in females than males, which might lead observers
to empathize more strongly with the attractive woman than the men. Attractive men’s faces
are typically associated with enhanced masculine facial characteristics and are considered to
possess fewer desirable personality traits compared with feminized faces. This could explain
more empathy shown to less attractive man. In conclusion, the study showed that the
attractiveness and sex of a model constitute an important modulator of pain empathy.Project
number: NN 10636174 Grant from the Ministry of Science and Higher Education, Poland
(1) Department of Experimental Neuropsychology, Institute of Cognitive and Behavioural
Neuroscience, Faculty of Psychology, University of Social Sciences and Humanities, Warsaw, Poland |
(2) Laboratory of Psychophysiology, Department of Neurophysiology, Nencki Institute of Experimental
Biology, Warsaw, Poland | (3) Laboratory of Brain Imaging, Neurobiology Centre, Nencki Institute of
Experimental Biology, Warsaw, Poland
Jankowiak-Siuda Kamila | [email protected]
EFFECTS OF CARBONIC ANHYDRASE INHIBITION AND ACTIVATION ON
LEARNING AND MEMORY IN MICE
Walker, Ellen, A (1) | Salkovitz, Matthew (1) | Draghici, Bogdan (1) | Kumar Sanku, Rajesh
Kishore (1) | Ilies, Marc, A. (1)
Cognition and memory deficits are common symptoms of many diseases affecting the central
nervous system. Carbonic anhydrase is a zinc enzyme that catalyzes the reversible hydration of
CO2 under physiological conditions and has a critical role in brain homeostasis and normal
cerebral function. We propose that carbonic anhydrase activators that can cross the bloodbrain-barrier will enhance learning and memory. Our objective is to design and synthesize a
library of novel potent and lipophilic carbonic anhydrase activators and test functional activity
using simple learning and memory models in mice. In the current studies, male, Swiss-Webster
mice were tested in a single day learning and memory operant conditioning task and a novel
object recognition task. In the operant task, the mice were placed within experimental
chambers and the acquisition and then the retention of a novel nose-poke response in the
presence of an audible tone was recorded. The mice were rewarded by Ensure solution for
responses that occurred during the tone. A recently designed lipophilic carbonic anhydrase
activator, BD117, was tested alone and in the presence of the carbonic anhydrase inhibitor
acetazolamide. Acetazolamide produced decreased retention of the novel nose-poke response
suggesting carbonic anhyrase inhibition can disrupt memory. However, BD117, the activator,
produced no overt adverse or behavioral effects that interfered with learning or memory and
produced a partial reversal of the inhibition produced by acetazolamide. In a standard novel
object recognition task with retention test intervals of 30 min - 1 hour, BD117 produced a small
enhancement of novel object exploration without altering total exploration. Taken together,
these data suggest carbonic anhydrase activation is a promising strategy to explore for memory
enhancement and the continued development of additional activators in this series.
(1) Temple University - United States
Walker Ellen A. | [email protected]
MOLECULAR LANDSCAPES OF INSTRUMENTAL AND PAVLOVIAN MEMORY
COMPONENTS SUBSERVING FOOD-SEEKING BEHAVIOUR
Goozee, Zara, Y (1) | Everitt, Barry, J (1) | Merlo, Emiliano (1)
The persistence of maladaptive cue-drug memories in abstinent addicts is a major factor in
inducing relapse and craving. Instrumental responding for an appetitive reward can be driven
by both Pavlovian and instrumental associative memory components. Once an associative
memory has been fully consolidated subsequent memory retrieval may trigger two processes,
reconsolidation or extinction, depending on reminder duration. Although these processes share
common properties, such as NMDA receptor dependency, they also have distinct molecular
signatures. Reconsolidation is dependent upon protein kinases and transcription factors, such
as Zif268. Conversely extinction is dependent on protein phosphatases, in particular calcineurin.
Here we separately triggered reconsolidation or extinction of the Pavlovian and instrumental
memory components of food-seeking behaviour and analysed the subsequent control each
component exerted over behaviour at test. Following this we explored the underlying
mechanisms using systemic NMDAR manipulations prior to memory retrieval. To elucidate these
mechanisms further, we analysed the molecular landscape during memory retrieval by
measuring calcineurin and zif268 levels in a range of candidate brain areas.
Following Pavlovian extinction alone animals showed cued-induced reinstatement at test,
compared to animals that also underwent instrumental extinction. The ability of the CS to
control behaviour was critically dependent on prior extinction of the instrumental component.
Calcineurin levels measured following a 1hr extinction session showed down-regulation in the
infralimbic cortex after all extinction conditions. Following reconsolidation of both memory
components calcineurin levels in the prelimbic cortex were decreased, whereas zif268 showed
a trend towards being up-regulated.
These results suggest an interaction between Pavlovian and instrumental control of foodseeking behaviour, with both components requiring extinction to reduce cue-induced
reinstatement. These findings have particular relevance in the context of cue-exposure therapy
for maladaptive memory disorders in humans, which relies on Pavlovian extinction and is
vulnerable to high rates of relapse.
Funded by a MRC Studentship.
(1) Behavioural and Clinical Neuroscience Institute - Department of Psychology - University of
Cambridge - UK
Goozee Zara Y | [email protected]
WHAT MAKES A COCAINE-ASSOCIATED MEMORY RECONSOLIDATE?
Vousden, George, H (1) | Rebecca J. Hubble (1) | Peña-Oliver, Yolanda (1) | Everitt, Barry, J
(1) | Milton, Amy, L (1)
Evidence suggests that memories for rewarding conditioned stimuli (CSs) can undergo a period
of lability after their retrieval, termed reconsolidation. This process is dependent on both
protein synthesis and NMDA receptor activation at the time of reactivation of the memory.
Blockade of either these processes impairs reconsolidation, indicated by an impairment of
memory recall several days later. Here we attempt to further these findings, investigating the
factors that contribute to the destabilisation of a cocaine-associated memory. Rats were
trained to lever press for a 20s light CS and a 0.25mg intravenous cocaine infusion. Animals
then underwent a reactivation session, where the CS-cocaine memory association was retrieved,
in the absence of cocaine, after being given a systemic injection of MK-801 (0.1mg/kg) or its
vehicle. The reactivation and training conditions were manipulated in order to investigate how
these factors contribute to whether the memory retrieval session results in its reconsolidation.
In Experiments 1 and 2 rats were trained on an FR1 schedule, where each lever press resulted
in the presentation of the CS and delivery of cocaine. Under these conditions neither noncontingent nor behaviourally contingent presentations of the CS in a reactivation session
appeared to result in the destabilisation of the memory. Subsequent experiments trained
animals under interval schedules where there are prolonged periods of drug seeking. In this
scenario, only the light CS predicts the delivery of cocaine and the lever press alone does not
predict delivery of cocaine. This may enhance the conditioned reinforcing properties of the
light CS and enhance the likelihood of reconsolidation occurring within a retrieval session
consisting of presentation of a cocaine paired cue. Data from these experiments provide insights
into the conditions that allow a retrieval session to result in destabilisation and subsequent
reconsolidation of cocaine-associated memories.
This work was supported by the Medical Research Council.
(1) Department of Psychology and BCNI - University of Cambridge - UK
Vousden George H | [email protected]
COGNITIVE IMPAIRMENT INDUCED BY DELTA9-TETRAHYDROCANNABINOL
OCCURS THROUGH HETEROMERS BETWEEN CANNABINOID CB1 AND
SEROTONIN 2A RECEPTORS
Viñals, Xavier (1) | Moreno, Estefanía (2) | Lanfumey, Laurence (3) | Pastor, Antoni (5) | de
la Torre, Rafael (5) | Gasperini, Paola (6) | Pardo, Leonardo (4) | Lluís, Carme (2) |
McCormick, Peter, J. (6) | Maldonado, Rafael (1) | Robledo, Patricia (5)
Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces
a variety of negative effects with major consequences in cannabis users that constitute
important drawbacks for the use of cannabinoids as therapeutic agents. For this reason there
is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies
carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2ARdependent dissociation in the beneficial antinociceptive effects of THC and its detrimental
amnesic properties. We found that specific effects of THC, such as memory deficits, anxiolyticlike effects, and social interaction are under the control of 5-HT2AR, but not its acute
hypolocomotor, hypothermic, anxiogenic and antinociceptive effects. In biochemical studies,
we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in
specific brain regions involved in memory impairment. Remarkably, our functional data shows
that co-stimulation of both receptors by agonists reduces cell signaling, antagonist binding to
one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a
switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the
sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were
able to disrupt receptor heteromerization in vivo leading to a selective abrogation of memory
impairments caused by exposure to THC. These data reveal a novel molecular mechanism for
the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC
from its beneficial antinociceptive properties.
(1) Neuropharmacology Laboratory - University Pompeu Fabra - Barcelona - Spain | (2) Department of
Biochemistry and Molecular Biology - Faculty of Biology - University of Barcelona - Spain | (3) INSERM
677 - Université Pierre et Marie Curie - Paris - France
Viñals Xavier | [email protected]
PHARMACOLOGICAL AND CHEMOGENETIC INVESTIGATIONS OF 5-HT2C
RECEPTOR FUNCTION IN RODENT TOUCHSCREEN VISUAL REVERSAL
LEARNING
Alsiö, J (1,2) * | Nilsson, R, O, S (1,3) * | Gastambide, F (3) | Wang, A, H, R (1) | Axelsson, S
(1) | Dam, S, A (1) | Mar, A, C (1) | Saksida, L, M (1) | Tricklebank, M (3) | Bussey, T, J (1) |
Heisler, L, K (4) | Robbins, T, W (1)
Reversal learning deficits are observed in psychiatric disorders such as schizophrenia and
obsessive-compulsive disorder and implicate circuitry including the orbitofrontal cortex (OFC)
and activity at 5-HT2C receptors (5-HT2CR). In this study, we developed a novel battery of
touchscreen reversal learning tasks for rats and mice and used pharmacological (systemic and
intra-OFC) and pharmacosynthetic manipulations to show that OFC 5-HT2CRs bidirectionally
modulate early perseverative-like reversal learning performance in rodents.
In Experiment 1-2, systemic 5-HT2CR antagonism through SB242084 dose-dependently
decreased errors during the early, but not during the late phase in 2-choice and 3-choice
reversal learning in rats. SB242084 did not affect visual discrimination learning. The effects
were replicated in the labs of both industrial (Eli Lilly) and academic (Cambridge University)
partners. In Experiment 3, we validated a novel touchscreen serial visual reversal task as
suitable for neuropharmacological microinfusion studies by showing that pharmacological OFC
inactivation impaired early but not late learning in this task. In Experiment 4, intra-OFC
SB242084 infusions reduced early errors without affecting late errors in this serial visual reversal
task. In Experiment 5, systemic SB242084 facilitated early reversal learning in mice, without
affecting late learning. In Experiment 6, we evaluated the effects of pharmacogenetic
activation of 5-HT2CR-positive neurons in the OFC of Ht2c-Cre mice after viral gene transfer of
rM3Ds DREADDs to this region; activating these neurons by clozapine-N-oxide impaired early
reversal, without affecting late reversal.
In sum, using novel touchscreen visual reversal learning paradigms, we show that OFC 5-HT2CR
antagonism and activation of OFC 5-HT2CR-containing cells decrease and increase early
perseverative-like behaviour, respectively. These findings may have translational relevance to
neuropsychiatric disorders associated with reversal learning impairments.
(1) Department of Psychology and Behavioural and Clinical Neuroscience Institute - University of
Cambridge - UK (2) Department of Neuroscience - University of Uppsala - Sweden | * J.A. and S.R.O.N.
contributed equally to this work | (3) Lilly Centre for Cognitive Neuroscience - Eli Lilly & Co Ltd - UK |
(4) Rowett Institute of Nutrition and Health - University of Aberdeen UK
Alsiö Johan | [email protected]
A NEW PARADIGM FOR HUMAN TASTE MEASUREMENT
Palmer, Kyle
We previously reported a high throughput system for in vivo measurement of taste quality and
palatability using rats as subjects (Palmer et al, 2013, PLoS ONE), and now have extended this
technology to rapid taste measurement in humans. The system is comprised of a robotic sample
delivery system, a touch-sensitive display (TSD) that records the subjects’ responses, and a
command computer that runs subject-interactive algorithms incorporating principles of operant
conditioning, signal detection theory, and game theory. To test the paradigm, a set of tastant
standards (TS), consisting of water and stimuli representing the basic tastes of sweet (100 mM
sucrose), sour (10 mM citrate), salty (100 mM NaCl), and bitter (1 mM quinine) were mapped to
specific locations in the visual field of the TSD. Three subjects were trained by the algorithms
to touch the taste-appropriate locations on the TSD for rewards (virtual poker chips) after
tasting 200 ul samples of TS automatically and randomly selected from a 96-well plate.
Following this initial training session, subjects then participated in a test session where they
were presented TS and a set of “test articles” consisting of concentration ranges of sucrose,
saccharin, stevioside, and SC45647. Correct association between taste stimulus and mapped
location was required for reinforcement on TS trials, whereas responses anywhere on the TSD
resulted in a poker chip on test article trials. The five TS were distributed as evenly as possible
across random 32 trials and the test articles across 64 random trials (totaling 96 trials for a 25
minute session). The resulting dataset generated concentration-response functions yielding a
sweetness potency rank order (and EC50s) of SC45647 (5 uM) > saccharin (3 mM) > stevioside (5
mM) > sucrose (61 mM). These and ongoing experiments demonstrate the potential for high
throughput taste testing in humans.
Opertech Bio Inc - USA
Palmer Kyle | [email protected]
DISCRIMINATIVE LEARNING AND LONG-TERM MEMORY IN ALZHEIMER'S
DISEASE: PERFORMANCE UNDER DIFFERENTIAL OUTCOMES
Estévez, Angeles, F (1) | Araya, Álvaro, A (2) | Barria, Jaime, A (2) | Bravo, Soledad, C (2) |
Molina, Michael (1) | Plaza, Victoria (2)
The aim of the present study was to continue exploring the potential facilitative effects of the
differential outcomes procedure (DOP), which has proved to be useful to enhance delayed face
recognition memory in people with memory impairments (elderly people and patients with
alcohol related amnesia or with Alzheimer's disease). In the experiment presented here, we
investigate whether this procedure would improve the performance of a discriminative learning
task related to an everyday activity in patients with Alzheimer' s disease. Participants had to
learn what pill to take at different times of day. Moreover, to explore whether the DOP may
also improve long-term memory, participants were asked to performance a memory task 1 day
and 1 week after completing the learning phase.The results obtained support previous studies
on the DOP and provide novel data about the potential use of this procedure as a therapeutical
technique to enchance long-term memory.
This research was supported by grants PSI2012-39228 from Spanish Ministerio de Economía y
Competitividad and CONICYT-FONDECYT 11140365 from Chilean Ministerio de Educación.
(1) Universidad de Almería - Spain | (2) Universidad Autónoma de Chile - Chile
Roman-Lopez, P | [email protected]
GAZE PATTERNS AND THEIR RELATION TO SOCIAL INTERPRETATION IN
YOUNG ADULTS WITH AUTISM SPECTRUM DISORDER
Lönnqvist, Linda 1 | Loukusa, Soile1 | Mäkinen, Leena 1 | Hurtig, Tuula 2, 3, 4 | Siipo, Antti
5 | Laukka, Seppo 5 | Väyrynen, Eero 6 | Mämmelä, Laura 3, 7 | Mattila, Marja-Leena2, 3|
Moilanen, Irma 2, 3 & Ebeling, Hanna 2, 3
Timing plays a fundamental role in social perception and communication, and difficulties
related to conversational timing have been observed in individuals with autism spectrum
disorder (ASD). In the present study eye tracking was used to investigate the precise temporal
features of gaze patterns in young, high-functioning adults with ASD. In addition, the relation
between gaze patterns and social interpretation was studied. The work was carried out in
collaboration with University of Oulu and Oulu University Hospital as a part of the
multidisciplinary research project Autism Spectrum Disorders – a follow-up study from childhood
to young adulthood.
The eye movements of 16 young adults with ASD and 16 control participants were measured
while they watched a semi-naturalistic video clip. The video was designed for this study and
depicted a socially complex communication situation. The participants answered questions
concerning the social and communicative content of the video, and their answers were scored.
For analysis of the eye-tracking data, communicatively relevant targets were identified and
marked in each frame of the clip. The distances between target points and gaze points were
counted, and the mean distances to each target compared group-wise. FDR adjustment was
used to correct for multiple comparisons.
The groups showed no differences in gaze values for any of the targets after adjusting p values
for the FDR. There is, however, reasons to suspect loss of true positives, so the possibility of
some real differences cannot be completely excluded. On the frame-by-frame level, FDR
adjustment eliminated significant correlations between social scoring and gaze values for most
targets. However, positive correlations for one target were found in the ASD group. Further
investigation is needed in order to clarify the discoveries of this exploratory study.
The work was founded by Academy of Finland, The Alma and K. A. Snellman Foundation,
Oulu, Finland, and Finnish Brain Foundation.
Child Language Research Center, Logopedics, Faculty of Humanities, University of Oulu, Finland 1;
PEDEGO Research Unit , Child Psychiatry, University of Oulu, Finland 2; Clinic of Child Psychiatry, Oulu
University Hospital, Finland3; Neuroscience Research Unit, Psychiatry, University of Oulu, Finland 4;
Learning Research Laboratory, Research unit of Psychology, Faculty of Education, University of Oulu,
Finland5; BME Research Group, Department of Computer Science and Engineering, University of Oulu,
Finland6; Department of Psychology, Faculty of Social Sciences, University of Jyväskylä, Finland 7
[email protected]
Lönnqvist Linda | [email protected]
LATERALIZED TYMPANIC TEMPERATURE RESPONSES TO LISTENING TO
WORDS
Mutlu, Murat (1) | Kaplan, Elif (2) | Şen, Umay (3) | Eren, Kübra (2) | Ertaş, Gökhan (4) |
Saybaşılı, Hale (1) | Canbeyli, Reşit (3)
Introduction: Studies show that the temperature measured from the tympanic membrane of an
ear reflects the ongoing activity of the ipsilateral hemisphere. Moreover, tympanic temperature
(TT) measurements provide lateralized responding to various stimuli.
Aim: To investigate the left hemisphere’s dominance in language processing in terms of
temperature.
Material and Method: Simultaneous recordings from both ears were made via a custom designed
device that uses digital temperature sensors placed in ear canals and TT was measured
continuously in three groups of female and male college students (n=20 each) who listened to
a list of 30 words (20 Turkish words and 10 words with both Turkish and English connotations)
and a fourth (silent control) group (n=9) that sat silently without exposure to the list. Initial
instructions given to the three groups listening to the word lists differed: experimental word
group was asked to remember the English words, number control group was asked to remember
the number of English words presented, and the third group (no instruction group) was just told
to listen to the list. Total duration of the list was approximately 11 minutes with 20-seconds
intervals between the words.
Results: Experimental word group displayed significantly higher left ear TT compared to the
right ear, a situation that was reversed in control subjects not given a special instruction (ttest, p<=0.01). The experimental word group also differed significantly with respect to the
difference in left and right TT measurements compared to the three control groups.
Furthermore, left ear’s temperature increase, from beginning to end of the experiment,
exceeded right ear’s temperature increase only in experimental group, in other three groups
right ear exceeds left ear’s temperature increase.
Conclusion: The left ear TT dominance in the experimental group is indicative of the dominant
differential activation of the left hemisphere in language processing.
(1) Institute of Biomedical Engineering - Boğaziçi University - Turkey | (2) Cognitive Science MA Boğaziçi University - Turkey | (3) Deparment of Psychology - Boğaziçi University - Turkey | (4)
Biomedical Engineering Department - Yeditepe University - Turkey
Mutlu Murat | [email protected]
INVESTIGATIONS INTO THE ROLE OF PREFRONTAL CORTEX REGIONS IN
PUNISHMENT LEARNING AND BEHAVIOUR
Jean-Richard-dit-Bressel, Philip (1) | McNally, Gavan, P (1)
Punishment involves the presentation of a negatively-valenced outcome contingent upon a
behaviour, which causes a subsequent suppression of that behaviour. The neural bases of this
phenomenon is poorly understood. Following findings that the basolateral amygdala (BLA)
encodes the aversive value of the punisher, we examined the role of the prelimbic (PL),
infralimbic (IL), and rostral insular cortex (RAIC) regions of the prefrontal cortex (PFC) in the
acquisition and expression of punishment, and aversive choice. Rats were trained to press two
individually-presented levers for food pellets. A punishment contingency was introduced for
one of the levers, such that pressing it caused the delivery of footshocks as well as pellets
(punished lever) while pressing the other lever continued to only deliver pellets (unpunished
lever). Rats rapidly reduced responding on the punished lever over the course of punishment.
Infusions of GABA agonists baclofen and muscimol (BM) into the aforementioned PFC regions
had no significant effects on the acquisition of suppression, expression of well-trained
punishment, or preference for the unpunished lever in an unpunished choice test. These
findings suggest that these prefrontal regions are not required for punishment encoding or
behaviour.
(1) University of New South Wales - Australia
Jean-Richard-dit-Bressel Philip | [email protected]
RELATIONSHIP BETWEEN BODY MASS INDEX, FAT MASS AND LEAN MASS
WITH FIBROMYALGIA IMPACT QUESTIONNAIRE IN A GROUP OF
FIBROMYALGIA PATIENTS
Roman-Lopez, P (1) | Sanchez-Labraca, N (1) | Estevez, AF (2) | Cardona, Diana (1)
Patients suffering from fibromyalgia (FM) had widespread musculoskeletal pain and stiffness,
fatigue, sleep disorders, cognitive impairment and other symptoms, which seriously affect their
quality of life evaluated by the Fibromyalgia Impact Questionnaire, making it difficult to
perform normal activities. Moreover, FM has been associated with a higher prevalence of
overweight and obesity than in the general population. The objective of this study was to
evaluate the relationship between body mass index (BMI), fat mass (fM) and lean mass (lM) with
quality of life in a group of FM patients. 60 FM patients, members of different FM associations
from Almeria (Spain) participated in our study. Some anthropometric measures were taken like
weight, height, BMI, body fat mass and lean mass. Our results showed that BMI, fM and lM
correlated differently with several items of the Fibromyalgia Impact Questionnaire. The present
findings reveal some interesting relationships, which need to be further investigated to improve
the management of FM patients.
(1) Department of Nursing Physiotherapy and Medicine - University of Almeria - Spain | (2)
Department of Psychology - University of Almeria - Spain
Roman-Lopez P | [email protected]
INVERSION EFFECTS ON THE LATERALIZATION OF BODY
REPRESENTATIONS
Lucafò, Chiara (1) | Tommasi, Luca (2) | Giacinto, Laura (2) | Marzoli, Daniele (2)
Several studies show an attentional bias towards others' right arm, which might be attributable,
both phylogenetically and ontogenetically, to the fact that most of our interactions occurs with
right-handed individuals. Therefore, the configural information of the body may include the
knowledge (in terms of both first-order relational information and structural information) that
the dominant hand is usually placed on the right side. The present study aimed at investigating
whether impairing configural processing by presenting upside-down human bodies could also
reduce the bias in favor of the right side of the body.40 participants took part in 3 different
experiments in which ambiguous stimuli representing human bodies performing manual actions
were shown, in two separate sessions, both upright and upside-down. The stimuli consisted of:
28 animations with point-light displays of biological motion; 52 static human silhouettes; 128
animations of a rotating human silhouette with one arm raised. Participants implicitly
attributed a right-handed or left-handed action to the stimuli by indicating their front/back
orientation (point-light displays and static silhouettes) or the clockwise/counterclockwise
direction of rotation (rotating silhouette). After calculating the proportion of actions perceived
as right-handed for each experiment, a repeated measures ANOVA was conducted in order to
test whether such an index was affected by the stimulus type and position (upright or upsidedown).
Participants perceived a greater number of right-handed actions when the stimuli were
presented upright than when they were presented upside-down. Such an inversion effect turned
out to be present in a similar way in all the three classes of stimuli.
The present results seem to confirm the hypothesis that the inversion of human bodies could
impair configural processing, thus eliminating the bias in favor of the right arm.
(1) Department of Neuroscience Imaging and Clinical Sciences - University of Chieti - Italy | (2)
Department of Psychological Health and Territorial Sciences - University of Chieti - Italy
Lucafò Chiara | [email protected]
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT STUDY OF
PROBIOTICS IN COGNITIVE AND EMOTIONAL SYMPTOMS OF
FIBROMYALGIA
Roman-Lopez, P (1) | Miras, A (3) | Sanchez-Labraca, N(1) | Cardona, D (1) | Cañadas, P (2) |
Estevez, AF (2) | Vivas, Ana B (4)
It has been shown that patients suffering from fibromyalgia (FM) and other so-called functional
somatic disorders have alterations in the intestinal microbial flora. Some studies have indicated
that pathogenic and non-pathogenic gut bacteria might influence mood-related symptoms and
cognition in animals and humans suggesting a possible relation between the intestinal microbial
flora and the brain. The main aim of the present study was to explore the impact of using
probiotics on the cognitive deficits (specially, executive processes) and emotional symptoms
usually observed in FM adult patients. 40 Fibromyalgia patients were randomized to receive
either a probiotic formulation or a placebo daily for eight weeks. Patients completed the Beck
Depression Inventory and the State-Trait Anxiety Inventory before and after the intervention.
A battery of cognitive experimental tasks was also administered to the participants in the study.
Results showed emotional and cognitive impairments that were improved following the
treatment with probiotics. This finding is discussed in terms of a gut-brain relationship that
may be mediated by microbes that reside or pass through the intestinal tract.
(1) Department of Nursing Physiotherapy and Medicine - University of Almeria - Spain | (3) Ecocentro
Almeria - Spain | (2) Department of Psychology - University of Almeria - Spain
[email protected]
Roman-Lopez P | [email protected]
MDMA IN ADOLESCENCE AFFECTS STRESS SUSCEPTIBILITY IN ADULTHOOD
Christensen, Anne, Karina (1) | Müller, Heidi, K. (1) | Sinning, Steffen (1) | Wiborg, Ove (1)
MDMA is a drug of abuse and is a common problem world-wide. The abuse of the drug is in
particular high in adolescence. MDMA causes long-term damage to the serotonergic system
resulting in impaired cognitive behaviour/function such as learning and memory as well as
higher cortisol release in stressful environments and increased depressive symptoms.
Although many studies have shown parallels between MDMA effects and stress, only a few
animal studies have investigated the consequence of combined exposure to MDMA and chronic
stress and the possible negative synergism. Pre-treatment with MDMA before exposure to
chronic unpredictable stressors have been shown to induce impairments in spatial learning.
We hypothesized that early life stress may lead to increased sensitivity to stress which later in
life can result in impaired learning and stress-induced depression by affecting monoaminergic
neurotransmission, mainly the serotonergic system.
Male Wistar rats were injected with MDMA during adolescence (about 6 weeks old) and later
exposed to chronic mild stress (CMS) for 6 weeks. Sucrose consumption was used as a measure
of anhedonia to assess the depression-like state in the rats. Anxiety, memory and learning were
assessed using behavioral tests (such as elevated plus maze, Y-maze and step down). Moreover,
specific biological markers were quantified to investigate whether MDMA in combination with
CMS affects specific biological markers in the neurotransmitter system.
Results: We found a significant increase in baseline body temperature after MDMA injection
(p<= 0.001) but no significant difference between control and MDMA animals in behavioral tests
before CMS supporting a subclinical state following MDMA. Preliminary results indicate a
combined behavioral effect of MDMA and CMS consistent with a more anxious and stresssensitive phenotype.
(1) Translational Neuropsychiatry Unit - Department of Clinical Medicine - Aarhus University Denmark
[email protected]
Christensen Anne Karina | [email protected]
RELATIONSHIP BETWEEN SUBJECTIVE WELL-BEING AND CORTISOL
AWAKENING RESPONSE: MODERATION BY SEROTONIN TRANSPORTER
GENOTYPE
Kursuncu, Simge (1) | Mavioglu, Nehir, R. (1) | Duman, Elif, A. (1)
Research investigating the well-being of individuals predominantly focused on negative
components of well-being, such as depressive symptoms and life stress, while very few studies
focused on the importance of positive factors, such as subjective well-being (SWB). For instance,
various studies were conducted on the effect of depressive symptoms on well-being and stress
response systems, such as the hypothalamus pituitary adrenal (HPA) axis. Some of these studies
also emphasized the moderation of these effects by a polymorphism in the serotonin transporter
gene (5-HTTLPR). In this study, we examined the effect of SWB on cortisol awakening response
(CAR), a prominent marker of HPA activity. In addition, we further tested the moderation of
this relationship by 5-HTTLPR genotype. Ninety-two (75% female) undergraduate students
completed measures on SWB and recent depressive symptoms and provided saliva samples for
genotyping. Participants’ salivary cortisol levels were measured on two days, 0-30-45 minutes
after awakening. 5-HTTLPR genotype was determined together with the rs25531 SNP and
categorized into two as the S-group with lower transcriptional activity (S/S and S/L genotypes)
and LL homozygotes with higher transcriptional activity. CAR was calculated as the average
area under the curve with respect to the ground. The results revealed that there was a
significant main effect of SWB on cortisol levels controlling for recent depressive symptoms (p
<= .05), such that individuals with high SWB showed higher CAR. However, there was no effect
of 5-HTTLPR genotype (p > .05). In addition to the main effect of SWB, there was a significant
interaction between SWB and 5-HTTLPR (p <= .01), such that those with high SWB and LL
genotype had higher CAR, while there was no change for the S-group. These results indicated
that genetic factors such as 5-HTTLPR may act as a moderator to change the relationship
between SWB and HPA activity, altering individuals’ vulnerability or resilience to psychological
disorders.
(1) Department of Psychology - Bogazici University - Turkey
Kursuncu Simge | [email protected]
BENZYDAMINE SELF-ADMINISTRATION IN THE RAT:
ELECTROPHYISIOLOGICAL EVIDENCE FOR A CENTRAL MECHANISM OF
ACTION
Avvisati, Riccardo (1) | Stendardo, Emiliana (1) | Meringolo, Maria (1) | Marinelli, Silvia (2) |
Badiani, Aldo (1,3)
Benzydamine (BZY) is a non-steroidal anti-inflammatory drug with local anesthetic and
analgesic properties used for the topical treatment of inflammations of oral and vaginal
mucosae. Benzydamine has been shown to reduce noradrenaline-induced prostanoid synthesis,
which may explain its anti-inflammatory effects. Virtually nothing is known about the effects
of BZY on the central nervous system. Yet, there are reports of voluntary systemic abuse of BZY
in drug addicts, resulting in a hallucinations and a state of euphoria. In the present study, we
investigated the reward proprieties of BZY using a procedure of intravenous self-administration
in the rat. We found that BZY has a powerful reinforcing effect and that this effect is greatly
facilitated in animals that had previously self-administered heroin and cocaine, indicating
behavioral cross-sensitization to the rewarding effects of BZY and major addictive drugs. We
also investigated the effect of BZY on cortico-accumbens synaptic transmission, using field
potential recordings in rat parasagittal brain slices. BZY dose-dependently reduced fEPSP
amplitude and paired pulse ratio, suggesting a presynaptic, inhibitory mechanism of action.
These electrophysiological effects of BZY were potentiated in rats that had previously selfadministered cocaine and heroin. Furthermore, BZY perfusion induced LTD-like responses in
the cortico-accumbens synapses, indicating that this drug can induce long-term synaptic
neuroplasticity in the reward circuitry of the brain. These findings provide firm evidence of the
abuse liability of BZY, especially in individuals with prior drug experience. Further research is
needed in order to shed a light on the molecular mechanism underlying the psychoactive and
reinforcing effects of BZY, to better understand its abuse potential, and possibly redefine the
toxicological profile of this drug.
(1) Sapienza University of Rome - Italy | (2) European Brain Research Institute - Rome - Italy | (3)
School of Psychology - University of Sussex - Brighton - United Kingdom
Avvisati Riccardo | [email protected]
THE ROLE OF CHRONOTYPE AND BIG-FIVE PERSONALITY FACTORS ON
CORTISOL AWAKENING RESPONSE
Ergin, Kardelen, C. (1) | Dedeoglu, Gizem (1) | Duman, Elif, A. (1)
Chronotype (morningness vs. eveningness of individuals) has been reported to alter stressrelated hormone levels, such as cortisol, and associated with various psychological and sleep
disorders. Several personality traits were examined in relation to both chronotype and cortisol
levels, but yielded inconclusive results. In this study, we investigated the associations between
chronotype, Big-Five personality traits (conscientiousness, extraversion, neuroticism,
agreeableness and openness), and cortisol awakening response (CAR) in a group of 92
undergraduate students (75% female). Participants completed the NEO-FFI personality
inventory for measuring Big-Five personality traits and Morningness-Eveningness Questionnaire
for measuring chronotype. In order to determine CAR, participants’ salivary cortisol levels were
measured on two days at 0, 30 and 45 minutes after awakening and average area under the
curve with respect to the ground was calculated. Among the personality traits investigated,
only conscientiousness and agreeableness was significantly associated with chronotype (p
<= .05), such that morningness was associated with both higher conscientiousness and
agreeableness. In terms of effect on cortisol levels, while there was no significant correlation
between chronotype and CAR directly (p > .05), higher conscientiousness was associated with
increased CAR (p <= .05). On the other hand, there was no significant correlation between
agreeableness and CAR (p > .05). Considering the potential regulatory effects of
conscientiousness on stress reactivity, our results emphasize the potential role of personality
factors in moderating the relationship between chronotype and CAR that may influence
individuals’ vulnerability to various disorders.
Funding: This project was funded by Bogazici University BAP-8249 grant awarded to EAD.
(1) Department of Psychology - Bogazici University - Turkey
Ergin Kardelen C. | [email protected]
ENHANCING EFFECTS OF SLEEP ON OBJECT RECOGNITION MEMORY
EVOLVE MORE SLOWLY THAN ON HIPPOCAMPUS-DEPENDENT PLACEOBJECT MEMORY
Sawangjit, Anuck (1) | Born, Jan (1) | Inostroza, Marion (1)
Previous studies showed that sleep enhances hippocampus-dependent memory, but not
hippocampus-independent memory. However, little is known about whether the consolidating
effect of sleep is preserved and how it develops over a prolonged period of time. In this study
we used spontaneous object-place recognition (OPR) as a hippocampus-dependent memory task
and novel-object recognition (NOR) as a hippocampus-independent memory task, to investigate
the temporal dynamics of the effect of sleep on the formation of remote memory. In the
sampling phase, rats were allowed to explore two identical objects in an open field arena for
10 minutes. Then, a 2-hour post-sampling interval followed in which the rats either slept (S
groups) or were sleep deprived (SD groups). For OPR testing additionally a 4-hour post-sampling
interval of sleep and sleep deprivation was employed. Memory was tested 1 week later on the
OPR task, and 1 or 3 weeks later on the NOR task. For memory testing (by preferential
exploration of novelty), the rats were again placed in the arena for 5 minutes in which either
one of the two sampling objects was moved to a different location (OPR task) or one of the two
sampling objects was replaced by a novel object (NOR task). On the OPR task, after the 1-week
retention interval only those rats that slept for 4 hours after the sampling phase showed
significant memory. On the NOR task, both sleep and sleep deprived rats showed similar
memory at the 1-week test but, surprisingly, at the 3-week test, NOR memory was significantly
stronger in the rats that had slept after the sampling phase. These results suggest that sleep
does not only benefit hippocampus-dependent memory but also memory not essentially
depending on hippocampal function. Yet, the effect for those latter memories appears to evolve
more slowly over time.
(1) Institute of Medical Psychology and Behavioral Neurobiology - University of Tübingen - Germany
Sawangjit Anuck | [email protected]
THE EFFECT OF SLEEP DURATION AND PERCEIVED STRESS ON CORTISOL
AWAKENING RESPONSE OF UNDERGRADUATE STUDENTS
Dedeoglu, Gizem (1) | Ergin, Kardelen, C. (1) | Duman, Elif, A. (1)
Previous literature reported conflicting results on the effect of sleep duration on awakening
cortisol levels. We hypothesized that one of the factors that would influence this relationship
would be individuals’ perceived stress levels. In order to test this hypothesis, salivary cortisol
levels of 92 undergraduate students (75% female) at 0, 30 and 45 minutes after awakening were
measured for two days. Participants also reported on perceived stress, sleep duration, and
awakening time. In terms of cortisol levels at awakening (t = 0 min), there was a main effect
of sleep duration such that those with less sleep had lower awakening cortisol (p <= .001).
However, there was no effect of perceived stress, or its interaction with sleep duration on
awakening cortisol (p > .05). When we investigated the cortisol increase after awakening, there
was a main effect of sleep duration (p <= .05) such that individuals who had less sleep had
higher cortisol increase. In addition, there was a significant interaction between sleep duration
and perceived stress (p <= .001) such that for individuals who had more sleep, perceived stress
did not affect the cortisol increase. However, for those who had less sleep, cortisol increase
was significantly lower in individuals with high perceived stress. In terms of cortisol area under
the curve with respect to the ground, there was a main effect of perceived stress (p <= .05)
such that individuals with high perceived stress had higher overall cortisol release. There was
also a significant interaction effect, indicating lower cortisol levels in individuals with high
perceived stress and less sleep (p <= .01). These results highlight the importance of combined
effects of perceived stress and sleep duration on cortisol reactivity that may enhance our
understanding of stress-related sleep and mood disorders.
This project was funded by Bogazici University BAP-8249 grant awarded to EAD.
(1) Department of Psychology - Bogazici University - Istanbul - Turkey
Dedeoglu Gizem | [email protected]
BEHAVIORAL, NEUROCHEMICAL AND FATTY ACIDS PROFILE IN RATS OF
DIFFERENT AGES
Sandini, Thaísa, M. (1) | Reis-Silva, Thiago, M. (1) | Moreira, Natalia (1) | Chaves-Filho, A, B.
(1) | Miyamoto, Sayuri (1) | Florio, Jorge, Camilo (1) | Spinosa, Helenice, S. (1)
Aging is a natural process that can promote behavioral and cognitive dysfunction and increase
the risk of dementia. Thus, it is a common interest on understanding the changes that occur in
behavior and encephalic aging, as well as also possible therapeutic approaches. The aim of the
present study was to evaluate differences in spontaneous aging performances in animal models.
Therefore, we tested Wistar rats with 3 months (young), 12 months (middle-aged) and 18
months (senescent) through behavioral, neurotransmitter and fatty acids analysis (Bioethical
protocol #3047/2013). The behavioral results showed that rats with 12 and 18 month of age
showed a decrease in rearing and grooming frequency in open field when compared to the
younger rats. We observed an increase of anxiety-like behavior in the elevated plus maze and
light dark box in rats with 12 and 18 month of age. On the Barnes maze, rats with 12 and 18
months showed impairment in learning during training sessions and at test day. In the
neurotransmitter analysis we observed decreased in the levels of dopamine, norepinephrine
and their metabolites, as well as GABA levels in prefrontal cortex, hypothalamus, hippocampus
and striatum in rats with 12 and 18 months of age when compared to the younger rats.
Chromatographic analysis revealed no differences between hydroxides (HDoHE) and
hydroperoxides (HpDoHE) levels of docosahexaenoic acid (DHA) and neither in fatty acid profiles
between different ageing. These results demonstrate that the behavioral changes observed and
mostly, the memory deficit observed in rats with 12 and 18 months of age are consistent with
decrease in the neurotransmitter levels. Thus, these results may be particularly important to
understand the memory impairment that occurs in middle aging, and also evaluate possible
therapies that can improve the spontaneous memory loss.
Grants: CAPES and CNPq
(1) University of São Paulo - Brasil
Sandini Thaísa M. | [email protected]
OREXINS/HYPOCRETINS REGULATE THC-INDUCED HYPOTHERMIA,
ANTINOCICEPTION AND ANXIOLYTIC-LIKE EFFECTS
Flores, África (1) | Julià-Hernández, Marina (1) | Maldonado, Rafael (1) | Berrendero,
Fernando (1)
Emerging evidence suggest the existence of a cross-talk between orexinergic and
endocannabinoid signalling. Thus, orexin signalling has been reported to stimulate the synthesis
of 2-arachidonoyl glycerol leading to retrograde inhibition, suggesting that endocannabinoids
might contribute to several orexin effects. Moreover, orexins modulate the rewarding effects
of cannabinoids through orexin receptor-1 (OXR1) signalling. In the present work we evaluated
the role of orexin transmission in the acute pharmacological effects induced by delta-9tetrahydrocannabinol (THC), the main psychoactive compound of the Cannabis
sativa plant. We employed orexin-deficient mice as well as C57BL6/J mice preteated
with the OXR1 antagonist SB334867 (5 mg/kg) or the orexin receptor-2 (OXR2) antagonist
TCSOX229 (10 mg/kg). Locomotion, hypothermia and analgesia were assessed following acute
administration of THC at 5 and 10 mg/kg. Additionally, anxiety-like behaviour was evaluated
using anxiolytic (0.3 mg/kg) and anxiogenic (5 mg/kg) doses of THC in the elevated plus maze.
THC-induced amnesic-like effect was also assessed in the object recognition task. Orexindeficient mice presented decreased THC-induced hypothermia and antinociception in the hot
plate test, as well as reduced anxiolytic-like effect. Conversely, no differences between
genotypes were observed in hypolocomotion and analgesia in the tail immersion paradigm, as
well as in anxiogenic- and amnesic-like effects induced by THC. Pretreatment with TCSOX229,
but not with SB334867, was able to mimic the findings observed in orexin knockout mice.
Immunoblot analysis revealed that orexin-deficient mice show normal CB1 levels in all brain
regions analysed. Immunofluorescence studies showed reduced THC-induced c-Fos expression
in the central amygdala and the preoptic area of orexin knockout mice. Therefore, our results
indicate that orexins modulate some cannabinoid-induced effects such as hypothermia,
supraspinal antinociception and anxiolysis, probably through OXR2 signalling and independently
from OXR1.
Funding sources: Instituto de Salud Carlos III, the Spanish Ministry of Science, the Spanish
Ministry of Education, and the Catalan Government.
(1) Laboratory of Neuropharmacology - Department of Experimental and Health Sciences - Pompeu
Fabra University - Barcelona
[email protected]
Flores África | [email protected]
THE INFLUENCE OF FACIAL EXPRESSION ON THE PROCESSING OF FOOD
VALENCE: AN ADAPTATION STUDY
Manippa, Valerio (1) | Padulo, Caterina (1) | Brancucci, Alfredo (2) | Tommasi, Luca (2)
Previous evidence showed that social interactions and emotional stimuli can influence desire,
intake and food preferences. The aim of our study was to understand indirectly, through a
cross-category adaptation paradigm, how the representation of faces and foods interact at a
cognitive level. Thirty-nine participants were presented with 144 couples of stimuli composed
by an adaptor (scrambled face or face with neutral, happy or disgusted expression; 5000ms)
and a test (natural and transformed pleasant food, or unpleasant food; 1000ms). The task
consisted in judging the value of the test (pleasant or unpleasant) by a key press. We expected
a “social” effect, i.e. a facilitation (low error rates and/or low reaction time) due to face
exposure (neutral expression compared to scrambled faces), and a congruent after-effect e.g.
a facilitation when adaptor and test had the same valence. The results showed a enhanced
performance for unpleasant foods with respect to pleasant foods, probably due to the presence
of an accurate system for the recognition of dangerous stimuli (as rotten food). A “social” effect
was also found, possibly caused by the polarizing function that faces have on attention. A
contrast after-effect (in terms of face and food valence) was found for happy face expression
that is not directly involved in food processing with respect to disgusting emotion. Finally, a
different influence of faces was found on pleasant food processing. In particular, while “social”
and congruent after-effect were present for natural food, a contrast after-effect was found for
transformed food.
(1) Department of Neuroscience and Imaging - Univeristy G. d'Annunzio of Chieti - Italy | (2)
Department of Psychological Health and Territory Sciences - Univeristy G. d'Annunzio of Chieti - Italy
[email protected]
Manippa Valerio | [email protected]
EFFECTS OF OPRM1 GENOTYPE ON OPIOID PHARMACOLOGY IN RHESUS
MONKEYS: IN VITRO AND IN VIVO EVIDENCE
Platt, Donna M. (1) | Vallender, Eric J. (1) | Rowlett, James K. (1) | Miller, Gregory M (2)
The A118G single nucleotide polymorphism (SNP) in the human mu opioid receptor gene
(OPRM1) has been associated with individual differences in vulnerability to addictions (opioid,
nicotine, alcohol), pain sensitivity, learning deficits, and responsivity to opioid therapeutics.
The pharmacological consequences of this SNP are not entirely clear and this lack of
understanding likely contributes to an abundance of conflicting findings. We capitalized on a
naturally-occurring, orthologous SNP (C77G) present in rhesus monkeys to evaluate the
consequences of this mutation on opioid pharmacology, both in vitro and in vivo. We conducted
saturation and competition binding assays with several opioid ligands (naloxone, naltrexone,
diprenorphine, DAMGO, morphine, beta-endorphin) using HEK-293 cells stably expressing mu
receptors encoded by the genes containing h118A, h118G, rm77C or rm77G alleles. In
saturation binding studies, the opioid ligands consistently were found to be 4 to 8-fold less
potent at the mutant allele in both species (118G/77G). Similar results were evident in
competition binding studies when the SNP-dependent difference in affinity for [3H]naloxone
was taken into account. To confirm that these potency differences were relevant in vivo, we
conducted an observation study with the selective mu agonist fentanyl in monkeys selected a
priori on the basis of OPRM1 genotype (CC or GG, N=6/genotype). The dependent measure was
the occurrence of the typical mu opioid-induced effect, scratching. Fentanyl increased
scratching in both genotypes in a dose-dependent manner and to a similar level. However,
consistent with the in vitro data, fentanyl was approximately 4-fold less potent at inducing
scratching in the GG monkeys. This latter finding also is consistent with human studies
indicating a “protective” effect of the 118G allele against other unwanted opioid-induced
behavioral effects. Understanding the effects of this common SNP on opioid pharmacology may
clarify the mechanism by which this SNP influences more complex behaviors. Supported by:
AA016828, AA019688
(1) Department of Psychiatry & Human Behavior - UMMC - Jackson | MS
Platt Donna M. | [email protected]
BENZODIAZEPINE CONSUMPTION BY MONKEYS, RATS, AND MICE
Rowlett, James K. (1) | Gunter, Barak, W. (1) | Follett, Meagan, E. (1) | Freeman, Kevin, B.
(1) | Platt, Donna, M. (1)
The addictive effects of benzodiazepines are a worldwide public health problem, yet selfadministration of these drugs in laboratory models is reported consistently to be moderate to
weak. Our research using rhesus monkey models has shown that as with humans,
benzodiazepines tend to maintain relatively modest but reliable levels of drug-maintained
behavior when compared with other drugs of abuse, such as opioids and stimulants. We recently
have initiated studies on benzodiazepine consumption in rodent species. In Sprague-Dawley rats,
midazolam (non-selective BZ) was used to establish responding under a 2-response, fixed-ratio
(FR) schedule of i.v. drug injection. Responding on the lever associated with drug injection was
greater than responding on an inactive lever, consistent with reinforcing effects. Moreover,
substitution of saline for midazolam resulted in a decrease in overall responding and no
differential responding on the drug-paired lever vs. inactive lever. Experimenter-administered
injections of benzodiazepines (midazolam, triazolam, clonazepam) did not reinstate responding
unless the drug-paired stimulus was present. We also have initiated a series of studies using
mice as subjects (C57Bl/6J strain). Due to the difficulties with i.v. self-administration in mice,
we instead chose a 2-bottle choice procedure in which two sucrose solutions (4% w/v) were
available 23 h/day, with one bottle also containing midazolam (0.004-0.064 mg/ml). The mice
drank up to 10 mg/kg/day in a concentration-dependent manner, and preference scores
(amount consumed on midazolam bottle/amount consumed on sucrose bottle) as well as
percent choice (midazolam consumed/total liquid consumed) showed maximum drug
preference slightly above indifference (e.g., maximum percent choice ≤ 60%). Overall, these
observations suggest that orderly yet moderate reinforcing effects or choice are observed across
monkeys, rats, and mice under a variety of conditions. Interestingly, in rats, reinstatement was
observed for drug-paired cues only, which is unique among drug reinforcers. Supported by NIH
grants DA011792, DA033795, and AA016179.
(1) University Mississippi Med Ctr - USA
Rowlett James K. | [email protected]
PERFORMANCE ON TASKS OF EPISODIC MEMORY IN THE RAT DIFFER
ACCORDING TO CONTEXTUAL CUES AND THE SPACING OF TRIALS: HOW
THIS MIGHT RELATE TO PLACE CELL ACTIVITY
Robertson, Barbara-Anne (1) | Eacott, Madeline, J (1) | Easton, Alexander (1)
Spontaneous Object Recognition tasks, a popular method of studying memory function in
rodents, capitalise on rats’ propensity to explore novel objects. Variations of these tasks have
been found to be reliant on different neural systems. Episodic memory in humans is our memory
for events in the past; in rodents, episodic memory is thought to be an integrated
representation of components in the environment which make up an event including the
memory for What (object) - Where (location) - Which occasion (context) (WWWhich). However,
a recent publication (Spiers, et al., 2015) found that whilst place fields remapped when wellhabituated rats were presented with a different visual context, the same cells failed to re-map
to contextually identical chambers in the absence of external visual cues.
Presently, rats were given a continuous trials version of the WWWhich task under two conditions
where context was defined in a way that mirrored conditions in which place cells do remap
(contextually rich) and in a condition where place cells do not remap (identical contexts). Rats
could identify the novel configuration when provided with contextually rich chambers, but
could not in contextually bare, identical chambers, a result that is consistent with the place
cell findings. Interestingly, performance differed when rats were given a version of the same
task in which trials were separated in time; rats that were previously unable to differentiate
the novel configuration in contextually identical chambers could when trials were spaced apart.
Comparing performance on these different versions of the WWWhich task allows us to
understand how context contributes to behaviour on tasks of episodic memory; behaviour was
consistent with the findings of Spiers et al, but only when trials were continuous. The results
of Spiers et al cannot currently explain why animals can perform the task when trials are spaced
in time.
(1) Durham University - United Kingdom
Robertson Barbara-Anne | [email protected]
ALCOHOL AND WAITING IMPULSIVITY: TRANSLATION FROM MOUSE TO
HUMAN STUDIES
Sanchez-Roige, Sandra (1) | Brown, Charlotte, A. (1) | Stephens, Dai, N. (1) | Duka,
Theodora (1)
Impulsivity is a multi-faceted phenomenon, with the various forms influencing excessive alcohol
drinking. In the current report, we concentrate on “waiting” impulsivity, the tendency for
premature responding in a reward-related task. In the 5-choice serial reaction time task
(5CSRTT), mouse strains predisposed to excessive alcohol consumption show heightened waiting
impulsivity. This finding suggests that impulsivity may predispose to poor control over alcohol
drinking. However, exaggerated impulsivity may also result as a consequence of acute alcohol
ingestion, or following long term alcohol abuse, and both acute doses of ethanol, and exposure
of adolescent mice to binge-patterns of alcohol lead to increased impulsivity.
Links between heightened impulsivity and excessive alcohol use have also been established in
humans. However, with no comparable methods between the species, it is unclear that data
obtained from animals correspond to aspects of impulsivity of relevance to human alcohol abuse.
We have developed a human homologue of the 5CSRTT, and shown that young adult binge
drinkers are impaired in the task. We now extend the mouse-human comparison to the effects
of acute alcohol. Young female and male human adult social drinkers (n=37, 20males; age 2134 years, M=24.18, SD=2.66) were given an acute moderate dose of ethanol (0.6 g/kg) over 30
minutes, and tested in the 5CSRTT 15 minutes later. Compared to placebo, alcohol impaired
accuracy of responding (baseline, or interval [ITI] of 5s prior to stimulus presentation, U(44)=86,
p=0.009; variable-ITI [vITI], U(44)=93, p=0.016) and response omissions (vITI, U(44)=72.5,
p=0.001), and increased numbers of premature responses (baseline, U(44)=105, p=0.04).
Collectively, the 5CSRTT offers a robust test of one form of impulsivity, waiting impulsivity that
readily allows translation of animal findings to humans. Impaired performance in the task may
offer a measure of impulsivity that represents both a premorbid risk factor for heavy drinking,
and a consequence of alcohol intake.
(1) School of Psychology - University of Sussex - Brighton UK
Sanchez-Roige Sandra | [email protected]
SPECIFIC EFFECTS OF SELECTIVE HIPPOCAMPAL LESIONS ON
EXPLORATION AND ONE-DAY PLACE LEARNING IN LARGE SHADOW-LIGHT
ARENA IN MICE
Pleskacheva, Marina, G. (1) | Deacon, Robert, M.J. (1) | Lebedev, Ilya, V. (1) | Permyakov,
Michail, G. (1) | Kuptsov, Pavel, A. (1)
The functional heterogeneity of the hippocampus along its longitudinal axis is well known.
There are data on differential involvement of septal (rostral) and temporal (caudal) subregions
in spatial learning and anxiety respectively, but this specificity is still a matter of debate.
We studied the effects of rostral and caudal bilateral cytotoxic (NMDA) lesions on exploratory
behaviour in heterogeneous (illumination, food/nofood) environment in C57BL/6 male mice.
Large open field arena (220 cm diameter, surrounded by a curtain with attached visual stimuli)
was with white center (diameter 150 cm) and brown wall zone. Moreover, a half of a whole
arena was light whereas remaining part was shaded. A bait (chopped hazelnut) was placed in
two adjacent quadrants (shaded and light) of central white part of arena, no baits were in two
other quadrants. The characteristics of trajectory in 5 trials (8 min, 10 min ITI) were assessed
in different zones: shadow&food, shadow&nofood, light&food, light&nofood. Mice with caudal
lesion dramatically increased locomotion especially after 1st trial and demonstrated lowest
thigmotaxis than other groups. Control spent more time in wall zone than rostral lesion group.
Changes of exploration manner (velocity, path meander etc) in different context zones were
found in all groups. However context effects were higher in lesioned mice. Illumination strongly
affected zone preference in caudal group, the animals preferred to explore arena and to feed
in shadow. Rostral lesion mice were more active than other groups in food zones. Initial
preference shadow&food zone changed in the course of experiment in control, they used both
feeding places at the last trials. Test trial (ITI= 24h, no food, even illumination) did not reveal
zone preference in rostral group. The findings confirm concepts of the functional heterogeneity
of the hippocampus, however lesion effects cannot be explained only in term of anxiety.
Supported by RFBR-13-04-00747.
(1) Department of Biology - Lomonosov Moscow State University - Russia
Pleskacheva Marina G. | [email protected]
THEORY OF MIND AND SELF-REPRESENTATION: COMMON AND DISTINCT
MECHANISMS
Nekovarova Tereza (1) | Fajnerova Iveta (1) | Kozakova Eva (1) | Tintera Jaroslav (2) | Rydlo
Jan (2) | Spaniel Filip (1) | Horacek Jiri (1)
The ability to represent and attribute mental states (knowledge, incentive, emotions) both to
oneself and others belongs to intrinsic human cognitive abilities. We study neuronal correlates
of theory of mind (an ability to attribute mental states to others) and self-perception (as
awareness of the characteristics and states that constitute one's self).
32 (17 males, 15 females) healthy adult subjects participated on the study. We examined them
using BOLD fMRI on Siemens Trio 3T scanner. The fMRI stimulation scheme consisted of 30 audile
stories (lasting for 33 sec), each followed by a question (lasted for 6 sec).
We used three different conditions: 1) Theory of mind (ToM) stories - concerning on analysis
and predicting behavior and motivation of others; 2) Self-perception (Self) stories - concerning
on one’s own behavior and 3) Instrumental stories, which were not based on analysis on human’s
behavior but can be answered by analysis of physical/instrumental patterns.
Owing the fact that there were significant inter-individual differences in categorization of
particular stories, we have used individual categorization of each participant for analysis.
Mental processing attributed to ToM, Self and Instrumental stories evoke large overlapping brain
areas but we could also find some specific regions connected specifically to individual tasks.
We detected activation in overlapping brain regions in cortical midline structures during both
Tom and Self conditions. However, Self-conditions activated specifically thalamus in both sides
and parts of default mode network (DMN), particularly its posterior part. During ToM-conditions
regions in cerebellum and right middle frontal gyrus were specifically activated.
This project was supported by GACR grants 13-23940S and 15-08577S, by Project Prvouk P34
and by the project „National Institute of Mental Health (NIMH-CZ)“ - grant number
ED2.1.00/03.0078 of the ERDF
(1) National Institute of Mental Health - Klecany - Czech Republic | (2) Radiodiagnostic and
Interventional Radiology Department - Institute for Clinical and Experimental Medicine - Prague Czech Republic
Nekovarova Tereza | [email protected]
CUSTOMIZING INDIVIDUAL NEEDS OF ACCESSING TEXT INFORMATION FOR
USERS WITH DYSLEXIA
Pařilová, Tereza (1,2) | Bayer, Jaroslav (3) | Hladká, Eva (1)
Between 10 and 17% of worldwide population suffers from dyslexia. In many papers, dyslexia is
identified as a specific learning difficulty (SpLD). However, according to WHO International
Disease Classification 10, dyslexia is treated as the R48.0 "Dyslexia and other symbolic
dysfunctions, not elsewhere classified" or as the F81.0 "Specific reading disorder" (therefor not
SpLD). Dyslexia can accompany another illness as its repercussion, for instance other
developmental/cognitive disorder, tumor or posttraumatic brain injury.
Development of technologies for users with reading or symbol disorder is neglected due to
statistically inconsistent number of users diagnosed across languages, dependency of the
technology on specific language principles or strict conditions of dyslexia diagnose tests.
However, not only diagnosed individuals may go through hard time while reading.
We are developing an application software that will allow Czech speaking users (users speaking
latin-alphabet languages, respectively) with dyslexia to access written information better in
any time and place, which also means easier socialization or access to education for them. We
suggest to fragment text into small parts using a dash sign. It will make visual syllables easier
to catch but still keep text consistent.
Such application will be gaining from individual letter similarity problems. It means (a) using
sets of visual tests to find individual needs of each user, (b) from results of such tests to learn
the pattern for text fragmentation, (c) accommodating text itself using a dash sign (-). The
individual customization will help to find the right pattern for fragmentation and the
application built upon these findings will serve not only to users with dyslexia but also to users
with temporary neurological disorders in consequence with a disease, trauma or operation.
(1) Department of Computer Systems and Communications - Faculty of Informatics - Masaryk
University - Czech Republic (2) Faculty of Medicine - Masaryk University - Czech Republic | (3)
Computer Systems Unit - Faculty of Informatics - Masaryk University - Czech Republic
Pařilová Tereza | [email protected]
A DOPAMINE-PREFRONTAL-ACCUMBENS CIRCUIT IS CRITICAL FOR
COCAINE REINSTATEMENT BEHAVIOR
James, Morgan, H (1) | Aston-Jones, G (1)
Introduction: Glutamatergic projections from the prelimbic area (PL) to nucleus accumbens
core (NAc) are activated by cues associated with drug reward but not natural reward
(McGlinchey et al., 2015). Anatomical evidence suggests that NAc-projecting PL neurons are
innervated by dopamine terminals originating from ventral tegmental area, however the
functional importance of this proposed dopamine-prefrontal-accumbens circuit for cocaine
reinstatement behavior remains to be investigated. Therefore, the present study sought to
examine the causal role of dopamine input onto NAc-projecting mPFC cells for cocaine
reinstatement behavior.
Methods: To first demonstrate that dopamine transmission in PL is necessary for cocaine cue
reinstatement, Sprague Dawley rats were prepared with bilateral PL-directed cannula, before
undergoing cocaine or sucrose self-administration training followed by 7+ days of extinction.
Prior to reinstatement testing, animals received either unilateral or bilateral infusions of the
D1/D2 antagonist fluphenazine (33.3mM/0.3µl) or vehicle.
We next used a pharmacological contralateral disconnection method to demonstrate that
dopamine recruits PL glutamatergic afferents to NAc to drive reinstatement behavior. Animals
was prepared with one guide cannulae in PL and another in either the ipsilateral or contralateral
NAc. Animals were trained and extinguished as above. Prior to reinstatement testing, animals
received an intra-PL microinfusion of fluphenazine as well as an intra-NAc infusion of a cocktail
of the NMDA/AMPA receptor antagonists AP-5 (33.8mM/0.3µl) plus CNQX (3.3mM/0.3µl).
Results: Bilateral infusions of fluphenazine in PL blocked cocaine but not sucrose reinstatement
behavior. Animals that received PL-directed fluphenazine and NAc-directed AP-5/CNQX in a
contralateral fashion exhibited significantly attenuated reinstatement compared to vehicleand ipsilateral-treated controls.
Conclusions: We provide the first evidence that mPFC glutamate neurons that project to
ipsilateral NAc are recruited by dopamine to drive cue-induced reinstatement of cocaine
seeking. This dopamine-prefrontal-accumbens pathway appears to be uniquely recruited by
drug-associated cues, as disconnection of this pathway had no effect on cue-elicited sucrose
seeking behavior.
(1) Brain Health Institute Rutgers University - USA
James Morgan H | [email protected]
A DOUBLE-COIL TMS STUDY OF IPSILATERAL DORSAL PREMOTORPREMOTOR CORTEX INTERACTION DURING ACTION PREPARATION
Luigi, Cattaneo (1) | Sara, Parmigiani (1) | Guido, Barchiesi (1)
Introduction: The ability to withhold a forthcoming action and to release it when appropriate
is a crucial feature in the life of a primate. In the present series of experiments we investigate
the possibility that in humans the dorsal premotor cortex (PMCd) could play a role in such
behavior. To do so we first devised a protocol to assess in vivo the ipsilateral PMCd-motor cortex
(M1) connectivity. We then tested the modulation of such connectivity in a delayed simplechoice conditional associative task, and in a delayed dual-choice conditional associative task.
Methods: we tested short-latency interactions between PMCd and the ipsilateral M1 with the
dual coil technique. The conditioning TMS (cTMS) was delivered over PMCd and the test TMS
(tTMS) was delivered over the mouth-related M1. Motor Evoked potentials were recorded via
surface EMG from the lips. cTMS+tTMS trials were intermingled with tTMS only trials. This
procedure was carried out in the first experiment at rest and in the second experiment during
the delay time in a single and dual choice delayed tasks.
Results: the first experiment provided evidence that PMCd exerts a powerful inhibitory effect
during rest on the ipsilateral mouth-related M1. This interaction occurred at an interval
between cTMS and tTMS of 6 ms. The results of the following experiments indicated that the
PMCd exerts an inhibitory effect on M1 during the delay period, which is reversed into excitation
by the go-signal.
Comments: our data are compatible with the possibility that, in a delayed visual conditional
associative task, PMCd is the premotor structure that actually inhibits the motor cortex during
the set period and possibly releases the programmed movement when the go-signal occurs.
(1) University of Trento - Italy
Luigi Cattaneo | [email protected]
A CRH-CRE RAT FOR STUDYING THE ANATOMY AND FUNCTION OF CRF
CIRCUITS
Messing, Robert, O. (1) | Pomrenze, Matthew, B. (1) | Hopf, Woodward, F (2) | Millan,
Zayra, E (2) | Dadgar, Jahan (1) | Kharazia, Viktor (2) | Janak, Patricia, H (2)
Corticotropin-releasing factor (CRF) is a central regulator of the stress response and a
modulator of aversive and appetitive behaviors. Neurons that express CRF are present in several
brain regions but are particularly concentrated in the paraventricular nucleus of the
hypothalamus, the central amygdala, and the bed nucleus of the stria terminalis (BNST). CRF
terminals are present in brainstem and subcortical regions where they impact autonomic
responses and motivated behavior. Previous studies have relied on tract tracing and CRF
receptor pharmacology to understand the anatomy and function of these neurons, but have
been limited by the inability to directly modulate their activity. Here, we generated a BAC
transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter
to permit genetic access to CRF neurons. By crossing Crh-Cre rats with a Cre-dependent GFP
reporter line, or by locally expressing Cre-dependent transgenes, we found that Cre+ neurons
of these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and in the
oval nucleus of the BNST. CeL Cre+ neurons project to parabrachial nuclei, locus coeruleus, the
oval and ventral BNST, the substantia innominata and the lateral hypothalamus. We detected
GABA responses in 44% of lateral but only 11% of medial CeA Cre− neurons in response to
optogenetic stimulation of CeL Cre+ neurons. We detected a similar proportion of lateral and
medial CeA Cre− neurons that express Fos following chemogenetic stimulation of Cre+ neurons.
These results suggest that CeL CRF neurons provide both inhibitory GABA and excitatory CRF
signals to other CeA neurons. These studies demonstrate the value of the Crh-Cre rat as a tool
for studying neural circuit function and physiology of CRF neurons.
(1) Institute for Neuroscience and College of Pharmacy-University of Texas at Austin-USA | (2)
Department of Neurology-University of California at San Francisco-San Francisco-CA-USA
Pomrenze, Matthew, B. | [email protected]
SLEEP BENEFITS THE CONSOLIDATION OF OPERANT EXTINCTION
Inostroza, Marion (1) | Bórquez, Margarita (2) | Contreras, María Paz (2) | Betancourt,
Ronald (2) | Born, Jan (1)
In operant conditioning the organism associates a behavior with its consequences (typically,
reinforcers); in extinction, the behavior declines as the reinforcer is removed. Extinction of
operantly conditioned behavior is typically specific to the extinction context, which is often a
limiting factor in the clinical application of extinction procedures, e.g., for treating substance
abuse. Sleep is known to support the consolidation of newly acquired memories. The objective
of this research was to examine whether sleep benefits the consolidation of operant extinction,
and also the context specificity of this influence. Three groups (n=16, each) of Sprague Dawley
rats were first trained in an operant conditioning task (lever press) in context A. On the next
day, extinction training was performed in context B. Extinction was followed by a 3-hour
retention interval that covered either a period of morning sleep (Sleep group), or of morning
sleep deprivation (SD group), or a period of spontaneous evening wakefulness (Wake group).
Following the retention interval, extinction was tested in context B and in a novel context C.
At test, the Sleep group showed significantly less recovery of the extinguished lever press
response than the two other groups, when tested in context B. However, when tested in the
novel context C, all groups displayed renewal of the response to a comparable degree. The
results indicate an enhancing effect of sleep on extinction of operantly conditioned behavior,
leaving the context specificity of extinction unchanged.
(1) University of Tübingen - Germany | (2) Universidad de Chile - Chile
Inostroza Marion | [email protected]
SLEEP TO REMEMBER A WHAT-WHERE-WHICH OCCASION
Oyanedel, Carlos, N. (1) | Born, Jan (1,2) | Inostroza, Marion (1)
The key issue of episodic memory in animals is to demonstrate memory for a unique episode,
ideally with information about what happened and where it happened. Our previous
experiments showed that sleep in rats supports the consolidation of hippocampus dependent
episodic-like memory, i.e., the ability to remember what happens, where and when (WWWhen).
It has been proposed that identifying episodic memory as a memory for what happened where
on a specific occasion (context) is a more encompassing definition than one that relies on
information about where an when an event occurred. To determine if sleep is likewise
important for the consolidation of the association of an object with its contextual information,
we tested rats on the “What-Where-Which occasion” task (WWWhich). The task consisted of
two separate 5-min sample phases (context A or B) with a 20-min interval in between, followed
by a 90-min retention interval that covered either regular morning sleep or sleep deprivation.
At the subsequent 5-min test, rats were presented with a familiar and novel object-locationcontext combination. Sleep during the retention interval, compared with the sleep deprivation
condition significantly enhanced retrieval in the WWWhich task. Following sleep deprivation,
rats did not display significant WWWhich memory. In combination our results show that sleep
does not only support episodic-like memory consolidation in terms of a What-Where-When
association, but also in terms of a What-Where-Which occasion association. Further
experiments are necessary to dissociate the individual components on the WWWhen and
WWWhich tasks, and to examine whether sleep differentially affects these components.
(1) Institute of Medical Psychology and Behavioral Neurobiology - University of Tübingen - Germany |
(2) Center for Integrative Neuroscience - University of Tübingen - Germany
Oyanedel Carlos N. | [email protected]
IMPLICATIONS OF INCREASED THETA ACTIVITY IN IL-6 TRANS-SIGNALING
DEFICIENT MICE
Oyanedel, Carlos, N. (1) | Inostroza, Marion (1) | Born, Jan (1,2) | Rose-John, Stefan (3)
The immune system contributes to the regulation of sleep. Research in this field focused on the
inflammatory cytokines interleukin-1 and tumor necrosis factor; however the role of
interleukin-6 (IL-6) in sleep regulation has been less intensely studied, with so far mixed results.
The reason might be due to the fact that the effects of IL-6 are carried via two different
pathways: classical via the membrane bound IL-6 receptor, and, trans-signaling via the soluble
IL-6 receptor. Previous experiments have shown that IL-6 transgenic mice, blocking the IL-6
trans-signaling in the body periphery (PEPCK mice) displayed less sleep, particularly during the
late light phase, and this was accompanied by decreases in absolute time and percentage (of
sleep time) in REM sleep. On the other hand, IL-6 transgenic mice, blocking the trans-signaling
in the brain (GFAP mice) did not show alterations in the sleep architecture, but a profound and
persistent increase in EEG theta activity. This shows that peripheral and central nervous IL-6
trans-signaling differentially influences brain activity. We further asked if this increased theta
activity in GFAP mice has behavioral implications; and if so, is this positively correlated with a
better performance of hippocampal-dependent tasks, but not with an increase in locomotion
compared with wild-type mice? We tested three different tasks: object-place recognition (OPR)
task, episodic-like memory (ELM) task and the activity on a running wheel (RW). No differences
between groups were found in the performance of the OPR and ELM. In addition, no differences
were found in locomotion. However, GFAP mice showed significantly better spatial memory
within the ELM task. In conclusion, increased theta is neither associated with an increased
locomotion, nor with a better performance of hippocampal-dependent tasks, but rather
associated with a better spatial memory, but only when it is integrated in a spatio-temporal
context.
(1) Institute of Medical Psychology and Behavioral Neurobiology - University of Tübingen - Germany |
(2) Center for Integrative Neuroscience - University of Tübingen - Germany | (3) Department of
Biochemistry - University of Kiel - Germany
Oyanedel Carlos N. | [email protected]
SHORT AND LONG-TERM EFFECTS OF SOCIAL STRESS ON MOTOR ACTIVITY
AND EXPLORATORY BEHAVIOR IN MALE MICE HOUSED IN ENRICHED OR
STANDARD ENVIRONMENTS
Redolat, Rosa (1) | Ramos-Campos, Marta (1) | Mesa-Gresa, Patricia (1)
Exposure to Environmental Enrichment (EE) can reverse changes induced by stress although few
studies have applied simultaneously these two interventions to the same group of animals. We
have evaluated short and long-term effects of exposure to EE or standard environment (SE) in
NMRI mice (n=128) submitted to chronic social stress (STRESS condition) or not (NO STRESS).
Phase I began on PND 28 and lasted 7 weeks. Mice were evaluated in a behavioral battery
including the hole-board task (5 min) and a running-wheel (15 min). Results obtained indicated
that in the hole-board, EE mice performed lower number of head-dipping (HD) than SE (p<=0.01).
Animals exposed to STRESS conditions also displayed lower number of HD (p<=0.01). Phase II
began on PND83, when the stress procedure had finished and lasted 4 weeks whereas mice were
maintained in EE or SE conditions. In this phase, results obtained in the hole-board and runningwheel indicated that neither the factor “Housing”, nor “Stress” or their interaction reached
significance. When the “Initial condition” (groups in which animals have ben maintained in
phase I) was taken into account, data indicated that animals whose initial condition was
EE+STRESS performed lower number of HD than EE+NO STRESS and SE+NO STRESS (p<=0.01). In
the running wheel, motor activity of EE+STRESS was lower than SE+STRESS and SE+NO STRESS
(p<=0.05). In Phase I, both exploratory and motor activity were reduced in EE groups in line
with previous results, although this change was not maintained at the end of Phase II. The group
EE+STRESS displayed changes in motor activity even when the social stress procedure had
finished. Future studies will need to increase the sample number in order to further explore
the complex interactions between stress and housing conditions observed in the current
research.
Acknowledgments: MINECO, Spain (PSI-2009-10410) and Generalitat Valenciana (GVACOMP
2010-173, PROMETEO/2011/048).
(1) Department of Psychobiology- University of Valencia - Spain
Redolat Rosa | [email protected]
ENCODING TIME INTERVALS IN ODOR FEAR CONDITIONING: ROLE OF THE
DORSAL STRIATUM
Mouly, Anne-Marie (1) | Boulanger, Bertolus, Julie (1) | Parrot, Sandrine (1)
Time perception is crucial to survival and goal reaching in humans and interval timing also
guides fundamental behaviors in animals. In pavlovian fear conditioning, an initially neutral
stimulus (the conditioned stimulus, CS) predicts the arrival of an aversive unconditioned
stimulus (generally a mild foot-shock, US) at a fixed time interval. It is now well documented
that in associative learning temporal relations between events are encoded. However the
neural network underlying the memory of time in fear conditioning remains poorly understood.
The aim of the present study was to investigate the role of the dorsal striatum (known to be
involved in time processing) in timing interval durations in odor fear conditioning in rats. We
used an experimental setup allowing the simultaneous recording of respiration, ultrasonic
vocalizations and behavior during training (10 Odor-Shock pairings, with a 20s CS-US interval).
This enabled us to detect the emergence of temporal patterns in the animal’s fear response
during acquisition, indicating that rats are able to encode CS/US interval duration after a few
training trials. In a previous study using 2-Deoxyglucose metabolic mapping, we showed that
odor fear acquisition was associated with an increase in 2DG uptake in the dorsomedial striatum
(Boulanger Bertolus et al, 2014). In the present work, we monitored DA concentration in the
dorsomedial striatum using intracerebral microdialysis during the acquisition session which
included 7 odor-shock pairings, 6 with a 20s CS-US interval and the last one with a 30s interval.
We observed a decrease in DA concentration at the onset of the pairings, which stabilized
throughout the 6 trials with a 20s CS-US interval and a further decrease when the interval
duration was changed to 30s. Finally, current experiments are carried out to investigate the
effect of pharmacological manipulation of the dorsomedial striatum on learning acquisition and
interval timing.
Funding: LIA CNRS-NYU LearnEmoTime, LABEX CORTEX (ANR-11-LABX-0042) of Université de
Lyon.
(1) Lyon Neuroscience Research Center - INSERM U1028 - CNRS UMR5292 - University Lyon1- Lyon France
MOULY Anne-Marie | [email protected]
CONSEQUENCES OF EARLY 5-HT1A RECEPTOR DELETION IN MALE AND
FEMALE MICE
Fülling, Christine (1) | Jabinet, Laura (2) | Simon, Huges (1) | Aminian, Esfandiar (1) |
Pinault, Alexadre (1) | Mittaud, Peggy (1) | Hornung, Jean-Pierre (1)
Serotonin 1a receptor knockout (5HT1aR-KO) mice exhibit increased anxiety-like behavior, a
feature also found in humans exhibiting an htr1a promoter polymorphism. Focusing on the
hippocampus - the region harboring the highest 5HT1aR expression in the forebrain - we
identified a role for this receptor in regulating dendritic arborization in CA1 pyramidal neurons.
Constitutive male 5HT1aR-KO mice show increased secondary branches of oblique dendrites and
altered synaptic plasticity. In contrast, female 5HT1aR-KO mice do not show these alterations,
suggesting a gender-dependent rescue mechanism.
Next we aimed at understanding whether these gender-dependent differences would translate
into differences in animal behavior. We observed that female 5HT1aR-KO performed similar as
compared to wild-type conspecifics. Male 5HT1aR-KO mice, however, displayed increased
anxiety-like behavior and impaired spatial learning in comparison to wild-type males.
Furthermore, as 5HT1aR-KO males exhibit abnormal social approach towards conspecifics,
which might be explained by possible difference in olfactory processing.
As anxiety, learning and memory as well as olfaction are influenced by adult neurogenesis we
are currently investigating to which extend the impaired survival of adult born neurons of
5HT1aR-KO animals is involved in the deficits seen in these animals. Furthermore, we are
investigating the possibility of an overall effect of the 5HT1aR-KO on cell survival. For that
matter we focus on natural cell death during the early postnatal period and after stressful
events. So far, we have identified differences in NR2B subunit expression in 5HT1aR-KO animals
to be involved in this process.
The gender difference described in this study as well as differences in olfactory processing add
to the phenotype of the 5HT1aR-KO animals and give further hints for the understanding of the
contribution of this receptor and downstream alterations of NR2B expression to anxiety-like
behavior and depression.
(1) University Lausanne - Switzerland | (2) University Zürich - Switzerland
Email: [email protected] |[email protected]
Fülling Christine | [email protected]
CALORIC RESTRICTION AFFECTS SPATIAL MEMORY AND BRAIN
METABOLISM IN YOUNG ADULT MICE
Steiner, Nadia (1) | Favrod Céline (1) | Magara Fulvio (2) | Pellerin Luc (1)
Caloric food intake restriction (CR) is a practice believed to result in many positive outcomes,
the best known of which is lifespan increase. However, the mechanisms of this phenomenon,
as well as its consequences on brain function, remain largely unknown. The brain is the organ
with the highest metabolic demand at rest, and subchronic glucose shortage can potentially
affect astrocytic glycogen storage and the main mechanism of neuronal energy supply, namely,
the astrocyte-neuron lactate shuttle (ANLS). Recently, a major role of the ANLS has been
demonstrated for memory formation and maintenance. In order to assess the effects of CR on
brain metabolism and cognition, we investigated the consequences of 5 weeks of CR on the
cognitive proficiency and on the expression of genes related to brain metabolism and to
synaptic plasticity. Because the effects of CR on lifespan seem to depend on the age at onset
of CR itself, we conducted the study on 3- and 12-months old mice. Mice were exposed either
to caloric restriction diet (CR) or ad libitum diet (AL). At the end of diet procedure, mice were
exposed to the Morris water maze test and the novel object recognition task to evaluate spatial
and recognition memory respectively. Expression levels of genes involved in brain metabolism
and in synaptic plasticity were assessed. Our preliminary results suggest that CR had a positive
impact only in young male mice on behavior, brain metabolism and synaptic plasticity, as well.
Young CR mice exhibit better spatial memory performances compared to AL. Further,
hippocampal mRNA expression levels of some genes involved in metabolism and synaptic
plasticity are significantly increased in young mice submitted to CR. In conclusion, our
observations suggest that dieting induced metabolic and synaptic adaptations improving
efficiency of brain metabolism; however, this appears to take place only in young animals.
(1) Department of Physiology - University of Lausanne - Switzerland | (2) Center for Psychiatric
Neuroscience - Centre Hospitalier Universitaire Vaudois - Switzerland
Steiner Nadia | [email protected]
ANIMAL MODEL OF PANIC DISORDER : THE IMPORTANCE OF EARLY
ENVIRONMENT
Luchetti, Alessandra (1,2) | Battaglia, Marco (3) | D'Amato, Francesca R. (1,3)
Clinical and preclinical studies demonstrated the importance of early environment in the
development of panic disorder (PD). PD patients show hyper-responsivity to CO2-enriched air
mixture and this physiological respiratory response represents a useful endophenotype that can
be used in animal research as well. The mechanisms that underlie this response include the
activation of acid-sensing chemoreceptors, identified in the brainstem and in the amygdala,
with increased ventilation, promoting the reinstatement of systemic pH.
We focused our study to set up a mouse model of PD based on the instability of the parental
environment. We used a repeated cross fostering (RCF) manipulation, consisting in repeated
adoptions of pups by different dams, during the first four postnatal days in outbred mice. We
evaluated the effect of RCF on: maternal behavior during the first week of pups’ life; ultrasonic
vocalizations of 8-day old pups to mum’s separation; respiratory response to hypercapnia in
youth and adulthood. RCF mice received adequate maternal care but showed higher separation
anxiety during development and hypersensitivity to CO2 enriched air mixture on respiratory
parameters. We evaluated two possible pharmacological rescue treatments for the respiratory
endophenotype: adult mice were injected with chlordiazepoxide, an anxiolytic compound, or
chlorogenic acid, a polyphenol that acts on acid-sensing ionic channels, before CO2 exposure.
Contrary to controls, RCF treated mice recovered from CO2 hypersensitivity with both
treatments. In addition we also demonstrated that RCF, but not control animals, showed
conditioned hyperventilation to a tone/context, when it has been previously associated with
CO2. This furthermore supports the aversion to 6% CO2 exposure in RCF, but not in control
animals.
(1) Cell Biology and Neurobiology Institute-CNR-Rome | (2) Sapienza University-Rome | (3) Laval
University-Quebec
Luchetti Alessandra | [email protected]
GEOGRAPHIC DIFFERENCES IN DISCOUNTING BEHAVIOUR AND THEIR LINK
TO CULTURE
Mahalingam, Vaishali (1) | Kosinski, Michal (2) | Stillwell, David (1)
What makes some cultures focused on long-term goals, whereas others are more focused on the
present? Research commonly finds that Eastern and Collectivist cultures are more impatient,
and so researchers have explained geographical differences in delay reward discounting as
being linked to cultural factors such as uncertainty avoidance and risk aversion. In a large
international sample (N = 52,906 from 20 countries), we study the link between cultural values
and delay discounting using three models of cultural differences at both the individual and
country levels: The East-West dichotomy, Hofstede’s cultural dimensions, and Schwartz’s
Values. Results showed that aspects of culture related to power and hierarchy (rather than
tradition and collectivism) showed the strongest positive associations with individuals’
discounting behaviour and this was consistent at both the country and individual level. These
findings support research on power which shows that experiencing power makes people feel
more connected to their future selves and so more able to resist the lure of an immediate
reward.
(1) University of Cambridge - United Kingdom | (2) Stanford University
Mahalingam Vaishali | [email protected]
HIPPOCAMPAL PKMZETA OVEREXPRESSION PROLONGED CONTEXTUAL
FEAR MEMORY AND POTENTIATED LTP MEASUREMENT
Schuette, Sven, R, M (1) | Fernandez-Fernandez, Diego (1) | Hobson, Scott (1)
In the last years, several studies have shown the influence of protein kinase M zeta (PKMzeta)
on long term potentiation (LTP) as well as behavior in rats. For example, inhibiting or silencing
PKMzeta in vitro and in vivo in hippocampus reduced synaptic transmission and led to impaired
performance in memory tasks. However, the influence of overexpression of PKMzeta has not
thoroughly been demonstrated. We used AAV5 mediated gene transfer to overexpress active
PKMzeta (WT) or a kinase dead PKMzeta (KD) in hippocampal neurons to assess its influence on
behavior, LTP and paired pulse facilitation (PPF) in hippocampal slices. Four weeks after
stereotactic injection, animals were trained for contextual and cued fear conditioning (CFC)
using a non-ceiling protocol and response was measured one week later. To distinguish the
associative fear learning and memory assessed in CFC from non-aversive episodic memory, we
additionally tested for performance in an Object location preference task (OLP).
Overexpression of PKMzeta WT but not PKMzeta KD led to prolonged memory storage in
contextual fear response whereas the cued fear response remained unaffected. Interestingly,
overexpression of PKMzeta did not result in an improvement in the performance of the rats
during the OLP task, suggesting differential association with memory domains.
Electrophysiologically, we identified a significantly strengthened LTP in hippocampal slices
from PKMzeta overexpressing animals, which was dependent on PKMzeta kinase activity but
not on de novo protein synthesis. Furthermore, an increased basal transmission were
identified in hippocampal slices overexpressing PKMζ WT, suggesting that PKMζ activity
potentiates synaptic transmission, possibly from post-synapse. However, no modulation of PPF
measurements has been found.
(1) CNS Research - Boehringer Ingelheim GmbH & Co KG - Germany
[email protected]
Schuette Sven RM | [email protected]
ANIMAL RESPONSE TO STRESS AND BLAST
Françoise Arnaud (1,2) | Eric Maudlin-Jeronimo (1) | Georgina Pappas (1) | Richard McCarron (1,2)
BACKGROUND: Combat imposes unique stresses on warfighters that may alter fight-or-flight
responses to acute stimuli at the time of combat. Moreover, stress can have direct influences on
neural activity and other aspects of physiology. The present study evaluated the impact of preimposed stress plus blast and hemorrhage on survival and physiological responses and coagulation
in a rat model.
METHODS: Rats were stressed by a 45 minute period of restraint-immobilization. Immediately
thereafter, they were anesthetized, and a catheter was introduced into the femoral artery for
blood pressure monitoring and sampling (baseline). The polytrauma was then produced by exposure
to a 75 KPa blast overpressure in a shock tube followed by a 35% estimated-blood-volume (EBV)
controlled hemorrhage. After 15 minutes of shock the animals received normal saline as
resuscitation fluid and were recovered and observed for either 3hrs or 72 hrs. The treatment
groups were Sham (No stress+No trauma), Non- stress+trauma), Stress+ No trauma and
Stress+trauma. Rectal temperature, heart rate (HR), mean arterial pressure (MAP) and peripheral
oxygen saturation (SpO2) were monitored, and blood tests were performed to assess complete
blood count and coagulation parameters (thromboelastometry, aggregometry and prothrombin
time). Survival rate was measured at 3hrs and 72 hrs. Major indicators of coagulation (CFT, PT,
ATIII, Aggregation) were unchanged following stress. ATIII and aggregation were elevated at 72 hrs
in all animals, possibly as an effect of surgical manipulation.
RESULTS: At baseline, corticosterone levels were similar in Stress and non-stress groups. At 72 hrs
the levels were significantly increased in the injured animals, indicating that the injury is a
stressor. There were no significant differences in survival between Stress or non-Stress groups at 3
hrs and 72 hrs. However, mortality increases significantly after injury in both Stress and non-stress
trauma groups. At baseline, all animals had similar HR, MAP, SpO2, and laboratory results. MAP
decreased acutely following injury, but at 72 hrs, MAP recovered to the value of the non-injury
control animals. Regardless of stress or injury, HR was reduced at 72 hrs in all groups. Major
indicators of coagulation (CFT, PT, ATIII, Aggregation) were unchanged following stress. ATIII and
aggregation were elevated at 72 hrs in all animals, possibly as an effect of surgical manipulation.
CONCLUSION: These preliminary data indicated no remarkable effect of stress on survival, vital
signs, lab results or coagulation in the absence of trauma. Trauma may be seen as a stressor,
evidenced only after 72 hrs. However, at 72 hrs, changes in aggregation may be due to the
experimental model (inflammation from surgery) rather than the direct effect of stress and
trauma.
This work was funded by DHP through work unit number 603115HP.2380.001.A1304 under approved IACUC animal protocol # 12OUMD-40S.
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department
of the Navy, Department of Defense, nor the U.S. Government.
This work was prepared as a part of officials duties. Title 17 USC provides that Copyright protection is not available for any work of the
United States Government, defined as work prepared by a military service member of employee of the U.S. Government as part of their
official duties.
(1) Naval Medical Research Center (NMRC), Silver Spring, MD; (2) Department of Surgery, USUHS, Bethesda, MD
Francoise Arnaud | [email protected]
DIFFERENTIAL COCAINE- AND HEROIN-INDUCED ACTIVATION OF
AMYGDALA PROJECTION NEURONS AS A FUNCTION OF CONTEXT
Contu, Laura (1) | Vassilev, Philip (2) | Koya, Eisuke (2) | Badiani, Aldo (1,2)
It has long been suggested that the setting of drug use plays a critical role in modulating the
rewarding effects of recreational drugs. However, until recently this hypothesis has rested
mostly on anecdotal evidence. Thus, our laboratory has developed an animal model to study
the effect of setting on drug self-administration (SA) in the rat: some rats reside in the SA
chamber (Resident rats) whereas other rats are housed in a distinct home environment cages
and are transferred to the SA chambers only for the testing sessions (Non-Resident rats).
Resident and Non-Resident rats exhibit a differential preference for drugs such as cocaine,
heroin, alcohol, and ketamine. In particular, we have shown, using a SA choice procedure, that
Resident rats tend to prefer heroin to cocaine, whereas Non Resident rats tend to prefer cocaine
to heroin (Caprioli et al. 2009). In order to shed light on the neurobiological mechanisms
underlying this phenomenon, we used double immunohistochemistry procedures to investigate
the effects of cocaine and heroin on the activity of phenotypically characterized neurons of the
striatal complex, the prefrontal cortex, and the amygdala. Resident and Non-Resident rats
were injected intraperitoneally with either cocaine or heroin and left undisturbed for 90 min.
Using a double immunofluorescence assay for Fos in combination with markers such as DARPP32, CaMKII, GAD67, parvalbumin, and calretinin, we found major differences in the ability of
cocaine and heroin to activate distinct populations of projection neurons and interneurons in
all brain areas, as a function of setting. In particular, we found a double dissociation in the
activity level of projection neurons of the Basolateral and Central Amygdala. These findings
suggest a pivotal role of the amygdala in the integration of pharmacological and environmental
information.
(1) Department of Physiology and Pharmacology - Sapienza University of Rome - Italy | (2) Sussex
Addiction Research and Intervention Centre (SARIC) - School of Psychology University of Sussex Brighton - UK
[email protected]
Contu Laura | [email protected]
FACILITATION AND IMPAIRMENT IN DIFFERENT SPATIAL MEMORY
PARADIGMS CANNOT BE INTERPRETED AS A MERE HIPPOCAMPAL
DYSFUNCTION IN GLUK3 KO MICE.
Micheau, Jacques (1) | Vimeney, Alice (1) | Mulle, Christophe (1) | Marighetto, Aline (1)
It has been recently shown that GluK3 kainate receptor is an essential subunit of presynaptic
autoreceptors that facilitate hippocampal mossy fiber synaptic transmission. GluK3 receptor
deficient mice (GluK3 KO) display markedly reduced short- and long-term synaptic potentiation
in hippocampal CA3 (Pinheiro et al., 2007). Here, we used GluK3 KO mice to investigate whether
the deletion of these receptors impact the mnemonic ability of the mice in different spatial
tasks. Interestingly, GluK3 KO mice learnt faster to locate a hidden platform in a water-maze
surrounded by a curtain with hanged cues and appeared to maintain the bias toward the target
quadrant when parts of these cues were removed. In the aftermath, a three-stage paradigm of
spatial discrimination in a radial maze was used to contrast relational/declarative from nondeclarative memory (Marighetto et al, 1999). Although the GluK3 KO mice learnt faster the first
stage of the task (Go-NoGo discrimination task) they were selectively and significantly impaired
in the second stage of the task (concurrent two-choice discrimination) that was assessing
relational memory and mnemonic flexibility, cardinal properties of long-term declarative
memory. The GluK3 KO mice were still impaired in the third stage of the task, namely 6-choice
discrimination (6 arms open) which is supposed to rely on procedural memory.
The current behavioral data compared to data on hippocampal lesions or aged animals
published by the group of Marighetto are suggesting that the phenotype of GluK3 KO mice does
not fit with a hippocampal alteration solely. Brain distribution of GluK3 receptors suggests a
more complex neural network potentially involving basal ganglia structures, including
substantia nigra, pars compacta and ventral tegmental area (Bischoff et al., 1997).
(1) University Bordeaux-INCIA-CNRS UMR 5287-France
[email protected]
Micheau Jacques | [email protected]
ELECTROPHYSIOLOGICAL AND BEHAVIORAL INVESTIGATION OF SPATIAL
MEMORY DEVELOPMENT
Jabès, Adeline (1) | Nelson, Charles, Alexander (2)
Spatial memory abilities emerge over the first years of life. The brain structures subserving
them also develop gradually. However, few studies have addressed how specific changes in
brain structure and function might underlie the emergence of these abilities.
We assessed the differential maturation of two spatial memory abilities: egocentric memory
(locations coded in relation to the body) and allocentric memory (locations coded in relation
to the surrounding environment) using behavioral and electrophysiological measurements.
Preliminary data suggested that 9-month-old (n=5) exhibit spatial recognition in egocentric but
not allocentric conditions. In contrast adults electrophysiological data (n=16) suggested spatial
recognition in both egocentric and allocentric conditions. We are currently testing 2-3-year-old
children, age at which allocentric memory is thought to emerge. Given the abnormalities
observed in the brain regions subserving spatial memory in several neurodevelopmental
disorders, it is particularly important to understand the normal development of this function
and brain structures subserving it.
(1) Institute of Psychology - University of Lausanne - Switzerland | (2) Harvard Medical School Division of Developmental Medicine - Boston Children's Hospital - Boston - MA - USA
Jabès Adeline | [email protected]
THE ROLE OF BRAIN MITOCHONDRIAL FUNCTION IN SOCIAL HIERARCHY
FORMATION
Hollis, Fiona (1) | van der Kooij, Michael, A (1) | Lozano, Laura (1) | Zanoletti, Olivia (1) |
Cantó, Carles (2) | Sandi, Carmen (1)
Social hierarchies are an integral component of socially living species. In such groups, an
individual’s social status is determined through competitive encounters for a limited resource
between conspecifics. Within a dominance hierarchy, the acquisition of a low social status
strongly reduces the individual’s well-being. Despite the consequences to health and physiology,
however, the ability of personality traits to predispose individuals to a particular social status
remains unclear. Furthermore, the underlying neurobiological mechanisms important for social
status remain largely unexplored. Here, we identify trait anxiety, as measured in the elevated
plus maze, as a predisposing factor for subordinate status in adult male Wistar rats. We also
associate differences in brain energy production with the effect of trait anxiety on social status.
High-anxious rats that are prone to become subordinate during a social encounter with a lowanxious rat exhibit reduced brain energy production under basal conditions. Our findings thus
highlight trait anxiety as a marker for a potentially vulnerable population and suggest a role for
brain energy in social status.
(1) EPFL - Switzerland(2) Nestlé Institute of Health Sciences SA - Switzerland
Hollis Fiona | [email protected]
EFFECTS OF ACUTE ADMINISTRATION OF A NEW PSYCHOACTIVE DRUG,
METHOXETAMINE, ON MOTOR ACTIVITY AND EMOTIONAL STATE IN RATS
Zanda, Mary T. (1) | Antinori, Silvia (1) | Fadda, Paola (1) | Fratta, Walter (1) | Chiamulera,
Cristiano (2) | Fattore, Liana (3)
Methoxetamine (MXE) is a novel psychoactive drug structurally which is perceived as safe by
users despite its severe adverse consequences. In this study we tested the behavioral effects
induced by acute intraperitoneal (i.p.) administration of MXE (0.5-5 mg/kg) in male rats. Data
showed that MXE transiently but significantly affects motor activity in a dose- and time-related
manner, with low and high doses inducing hyper- and hypomotility, respectively, during the
first 20-min after administration. As compared to controls, MXE dose-dependently also
decreases the startle amplitude of rats in the pre-pulse inhibition test, which provides an
operational measure of sensorimotor gating reflecting the ability of an animal to successfully
integrate and inhibit sensory information. At the highest dose tested (5 mg/kg), MXE induces
transient analgesic effects after 30/45-min from administration, as revealed by tail flick and
hot plate tests. MXE 5 mg/kg induces anxiety-like state too, as suggested by the higher amount
of time spent by MXE -treated rats in the closed arms of the elevated plus maze (EPM) with
respect to VEH-treated animals. We then tested MXE in the marble burying test (MBT), an
animal model frequently used for assessing either anxiety-like and/or repetitive-like behaviors
in rodents as well as neophobia and/or obsessive-compulsive behavior. Rats treated with MXE
0.5 and 1 mg/kg buried a significantly higher number of marbles than controls, suggesting an
anxious and/or obsessive-compulsive trait. Moreover, in the forced swim test (FST), MXE 5
mg/kg reduces immobility and climbing while significantly increasing swimming activity, which
suggests an antidepressant effect. Altogether, our results indicate that MXE differentially alters
spontaneous motor activity, induces analgesia and spatial anxiety (EPM) and increases
swimming time (FST) at high doses, while inducing repetitive/perseverative (obsessivecompulsive) behaviors (MBT) at low doses.
Funded by Fondazione Banco di Sardegna (2014) and Joint Project 2012 (26753) from University
of Verona.
(1) Depart. of Biomedical Science - Div. Neuroscience and Clinical Pharmacology - University of
Cagliari | (2) Neuropsychopharmacology Laboratory - Division of Pharmacology - University of Verona |
(3) CNR Institute of Neuroscience - Cagliari Italy
Zanda Mary T. | [email protected]
ROLE OF L-DOPA IN CUE-INDUCED REINSTATEMENT OF COCAINE-SEEKING
BEHAVIOR IN RATS
Antinori, Silvia (1) | Fattore, Liana (2,3) | Fratta, Walter (1,2) | Gessa, Gian, L. (1,2,4) |
Devoto, Paola (1,2,4)
Clinically, dopamine agonists have been proposed as therapeutic tool for cocaine addiction and
positive results have been obtained with L-DOPA, the dopamine metabolic precursor, especially
when associated with behavioral therapy. However, until now no preclinical study was available
on the effects of L-DOPA in animal models of drug self-administration. We recently
demonstrated that administration of L-DOPA was able to suppress cocaine-induced
reinstatement of cocaine-seeking behavior in rats. In this follow-up study we verified whether
L-DOPA suppressant effect was as effective on cue-induced reinstatement of cocaine-seeking
behavior as on drug-induced reinstatement.
Male rats were trained to daily self-administer cocaine (0.5 mg/kg/infusion) intravenously for
2 hours under a fixed-ratio 1 schedule of reinforcement, each cocaine infusion being associated
with visual and auditory cues. After an extinction training, animals underwent cue-induced
reinstatement test sessions. An exposure to a cue priming immediately before starting the
session readily reinstated cocaine-seeking behavior to the pre-extinction responding level, an
effect efficaciously reversed by intraperitoneal pretreatment with L-DOPA (50 mg/kg).
Since extended access to cocaine self-administration may produce symptoms characteristic of
addiction that are not seen following more limited drug access, animals were allowed to resume
responding for cocaine during extended (6 hours) sessions. As expected, cocaine selfadministration was promptly reacquired. Once a stable drug intake was reached, rats were
pretreated with L-DOPA either on the last day of cocaine self-administration training or during
cue-induced reinstatement of drug-seeking behavior. Results showed that L-DOPA did not affect
cocaine intake but prevented cocaine-seeking reinstatement induced by re-exposure to cue
priming.
Our findings showed that L-DOPA does not affect voluntary cocaine intake in rats; yet, it may
be useful in preventing relapse to cocaine use since it is able to prevent both drug- and cueinduced reinstatement of cocaine-seeking.
(1) Dpt. of Biomedical Sciences Division of Neuroscience and Clinical Pharmacology - University of
Cagliari Italy | (2) Centre of Excellence “Neurobiology of Dependence” - University of Cagliari Italy |
(3) CNR Neuroscience Institute - Cagliari Italy
Antinori Silvia | [email protected]
IMPAIRED MATERNAL BEHAVIOUR BY ABERRANT DOPAMINE-PROLACTIN
SIGNAL
Shimokawa, Noriaki (1,2) | Sairenji, Taku (1) | Koibuchi, Noriyuki (1)
Cbl-interacting protein of 85 kDa (CIN85) is a scaffold/multi-adaptor protein implicated in the
regulation of receptor endocytosis, cell division and the cellular cytoskeleton. Recently, we
reported that mice deficient of CIN85 expression show hyperactive phenotypes. As a molecular
explanation of this phenotype, the absence of striatal CIN85 causes decreased dopamine
receptor endocytosis in striatal neurons in response to dopamine stimulation. We show here
another phenotype besides the hyperactivity of CIN85 knockout (KO) mice that of maternal
neglect to the newborns. Even though there is no difference in the number of live births from
CIN85 KO homozygote, heterozygote and wild-type mothers, respectively, almost all pups born
to CIN85 KO homozygote mothers have died within two days of birth. Moreover, despite of the
fact that no defect in the mammary glands of CIN85 KO mother mice was found, milk was not
detected in the stomachs of most pups. Importantly, when measuring the plasma levels of
prolactin (PRL), we found significantly decreased plasma PRL levels in CIN85 KO mice compared
to heterozygote and wild-type mice. We also analyzed dopamine levels in the hypothalamus of
CIN85 KO mice, since hypothalamic dopamine tonically suppresses PRL secretion from the
pituitary. We detected CIN85 KO animals to contain a two-fold increase in the levels of
dopamine in the hypothalamus, as compared to wild-type mice. PRL injection in CIN85 KO mice
could however partially rescue the defect in maternal behavior. Our findings indicate a loss of
CIN85 function leads to a neglect-like behaviour due to aberrant dopamine-PRL signaling.
(1) Dept. of Integrative Physiology - Gunma University Graduate School of Medicine - Japan | (2) Dept.
of Nutrition - Takasaki University of Health and Welfare - Japan
Shimokawa Noriaki | [email protected]
EFFECT OF ODQ ON BDNF IMMUNOHISTOCHEMISTRY STAINING IN MICE
Köktürk, Sibel (1) | Akar, Furuzan (2)| Mutlu, Oguz (2) | Ulak, Guner | Erden, Faruk |
Celikyurt, Ipek K
Since the discovery of nitric oxide (NO) as an intercellular messenger in the central nervous, its
way to modulate cognitive functions and mood is subject of intense research. The evidences
suggests that the L-arginine/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine
monophosphate (cGMP) signaling pathway in the hippocampus plays an important role in
memory processing and depression. The soluble guanylyl cyclase inhibitor1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) induced dose-dependent antidepressant-like
effects in previous studies.
The brain-derived neurotrophic factor (BDNF) is widely expressed in all brain regions, where it
has important effects on neuroprotection, synaptic plasticity, mammalian food intake-behavior,
and energy metabolism. Several studies shows that inhibition of the L-arginine/NO/sGC/cGMP
pathway exerts antidepressant-like effects by increasing of the BDNF levels in the hippocampus.
Diminished levels of the BDNF, particularly in the hippocampus has been also observed after
exposure to stress.
Therefore the aim of this study was to investigate the effects of ODQ on the BDNF
immunohistochemistry staining in CA1 of the hippocampus in the brain of naive mice. Mice were
treated intraperitoneally by ODQ (3 mg/kg) and physiological saline (n=6/group).
The hippocampal sections were collected and processed for the BDNF immunohistochemistry
and Hematoxylin-eosin (H&E) stainings. The BDNF distribution in the CA1 were then detected,
and compared between in the groups. Our results showed that the ODQ3 group significantly
increased the BDNF distribution than the sham group in the CA1. Our findings suggest that the
potential antidepressant effects of ODQ in previous studies can be correlated with its increasing
effect on BDNF distribution. Further studies should be done to support our results.
(1) Department of Histology and Embriyology - Medical Faculty - Ordu University - Ordu -Turkey | (2)
Kocaeli University Medical Faculty- Department of Pharmacology - Kocaeli - Turkey
NUMERICAL COMPETENCE IN RHESUS MONKEYS (MACACA MULATTA)
Rejlova, M. (1,3) | Landova, E. (3) | Rokyta, R (2) | Nekovarova, T. (1,2,3)
Numerical competence belongs between the cognitive functions, which we can find - in
different levels - in various animal species. Animals perform numerical competence in various
processes, as:”subitizing”, relative numerosity discrimination or summation. The other complex
numerical operations are: ordinality, transitivity or cardinality.
We focus on numerical competence in rhesus monkeys (Macaca mulatta).
We will test monkeys in equivalent numerical tasks of different level of abstraction.
First, we test relative numerosity discrimination in task with real objects. We have trained the
monkeys in repeated one-choice tasks. The monkeys have to choose one of two cups in which
we had visibly hide different number of food reward (raisins, nuts or pieces of fruits). We
observed, whether the monkeys were able to choose a bigger rewards. The number of objects
(rewards) varied between 1 and 9. Monkeys had been previously trained in object-permanence
experiment, so they were familiar with the task.
In the second experiment, we test the monkey whether they prefer quality or quantity - the
monkeys choose between one bigger reward and few smaller; the total weight of both types of
rewards would be the same.
Our preliminary data demonstrated that tested monkeys are able to perform relative
numerosity discrimination with the real objects.
In the following experiments we will study complementary tasks, but with stimuli, which are
not directly the rewards themselves. We will present as stimuli the points of various size and
shapes to see whether the monkeys would recognize the higher number of stimuli. Analogously,
we will test whether the monkey prefer bigger stimulus or few stimuli of the smaller size.
This project was supported by GAUK 1508414, Project Prvouk P34 and by the project „National
Institute of Mental Health (NIMH-CZ)“ - grant number ED2.1.00/03.0078 of the ERDF
(1) National Institute of Mental Health, Klecany, Czech Republic | (3) Ecology and Ethology Research
Group, Department of Zoology, Faculty of Natural Science, Charles University in Prague, Prague,
Czech Republic | (2) Department of Normal, Pathological and Clinical Physiology, Third Faculty of
Medicine, Charles University in Prague, Prague, Czech Republic
Rejlova M. | [email protected]
[123I]FP-CIT (DaTscan) SPECT, SMELL AND TASTE FEATURES IN PATIENTS
WITH PARKINSONIM SECONDARY TO NORMAL PRESSURE HYDROCEPHALUS
Cecchini, Maria Paola (2) | Matinella, Angela (1) | Dallocchio, Carlo (3) | Pacchetti, Claudio
(4) | Tinazzi, Michele (1)
Aims: Parkinsonism in idiopathic normal pressure hydrocephalus (INPH) is characterized by a
small-stepped, broad based gait, with features similar to degenerative parkinsonism. Therefore,
differential diagnosis between INPH and degenerative parkinsonism can be challenging. The
functional integrity of dopaminergic nigrostriatal pathway can be studied with single photon
emission computed tomography (SPECT) imaging by using ligands ([123I]FP-CIT) of pre-synaptic
dopamine transporter (DAT). Several [123I]FP-CIT SPECT studies have reported a significant loss
of striatal DAT binding in patients with pre-synaptic parkinsonism. The aim of the present study
is to evaluate dopaminergic system with SPECT imaging in patients with parkinsonism secondary
to INPH and to assess smell and taste functions in these patients.
Matherials and Methods: We assessed ten patients with parkinsonism secondary to INPH. Eight
of them underwent [123I]FP-CIT DaTscan SPECT, while all patients had olfactory evaluation and
taste assessment with “Sniffin’ Snick Extended Test” and “Taste Strip” tests respectively.
Results: All [123I]FP-CIT DaTscan SPECT analysis resulted normal. Regarding smell evaluation,
three patients were normosmic, five hyposmic and two with functional anosmia. Finally, all
patients were normogeusic except two (who presented mild hypogeusia).
Discussion: this study show that there is no any nigrostriatal deficit in parkinsonism secondary
to INPH, suggesting that other mechanisms are involved in the origin of parkinsonism in this
condition. The abnormal olfactory function in a high proportion of our patients could be due to
the intermittent increase of intracranial pressure in INPH: the chronic interference of olfactory
system with fluid dynamics could act on olfactory function.
Conclusions: This preliminary results suggest that SPECT DAT SCAN could be an useful diagnostic
tool in differentiating INPH from degenerative parkinsonism.
(1) Department of Neurological and Movement Sciences - Neurology Unit - University of Verona Verona - Italy | (2) Department of Neurological and Movement Sciences - Anatomy and Histology
Section - University of Verona -Verona - Italy | (3) Division of Neurology, Ospedale Civile - AO
Pavia/Voghera - Italy | (4) Parkinson's Disease and Movement Disorders Unit - National Institute of
Neurology Foundation "C. Mondino" - Pavia - Italy. Interdepartmental Research Center for
Neurodegenerative Disease - National Institute of Neurology Foundation "C. Mondino" - Pavia - Italy
Email: mariapaola cecchini univr it
Cecchini, Maria Paola | mariapaola cecchini univr it
PASSIVE ROBOT-ASSISTED UPPER LIMB TRAINING IN CHRONIC STROKE
PATIENTS: QUANTIFICATION OF EEG POWER CHANGES AND UPPER LIMB
RECOVERY.
Gandolfi, M. (1) | Formaggio, E. (2) | Geroin, C. (1) | Storti, S, F. (3) | Boscolo, Galazzo, I.
(4) | Bortolami, M. (1) | Waldner, A. (5) | Manganotti, P. (6)
So far, few studies have reported the effects of robot-assisted tasks passive upper limb training
on the modulation of EEG cortical activity during in chronic stroke patients.
The aim of the study was to evaluate changes in EEG power and upper limb recovery after
passive robot-assisted hand training in chronic stroke patients.
A single-group treatment trial with baseline comparisons was performed. Seven outpatients
with upper limb paresis received 21 training sessions consisting of bilateral forearm pronosupination and wrist flexion-extension training (1600 repetitions/session). A blinded rater
assessed the patients over a 2-week baseline period twice before, once after training, and once
at 1-month follow-up. The assessment included validated clinical scales and a standardized
video-EEG system combined with a robotic device. The EEG data were compared with those of
8 right-handed control subjects tested under the same protocol paradigm.
After training improvements on the Fugl-Meyer Motor Assessment Scale, Motricity Index and
Modified Ashworth Scale were found. Training effects, as measured by the Fugl-Meyer Motor
Assessment Scale and Motricity Index, were maintained at follow-up. Behavioral improvements
paralleled the changes in the modulation of alpha and beta event-related
synchronization/desynchronization (ERS/ERD). After rehabilitation, activation included the
ipsilesional primary sensorimotor cortex in five patients out of six.
To conclude passive robot-assisted training program may improve upper limb function and
promote changes in the modulation of alpha and beta ERS/ERD of areas related to movements
of the affected limb in chronic stroke patients.
(1) Neuromotor and Cognitive Rehabilitation Research Centre (CRRNC) - University of Verona - Italy |
(2) Department of Neurophysiology - IRCCS Fondazione Ospedale San Camillo - Venice - Italy |
(3) Department of Computer Science - University of Verona | (4) Institute of Nuclear Medicine University College London - UK | (5) Department of Neurological Rehabilitation - Private Hospital Villa
Melitta - Bolzano - Italy | (6) Section of Neurology - Azienda Ospedaliero-Universitaria Ospedali Riuniti
Trieste - Italy
Gandolfi M. | [email protected]
SEX AND EARLY MATERNAL ENVIRONMENT MODULATE VULNERABILITY TO
SOCIAL AND METABOLIC CHALLENGE IN CONDITIONAL NPY1R KO MICE
Paterlini, Silvia (1) | Panelli, Riccardo (1) | Gioiosa, Laura (1) | Parmigiani, Stefano (1) |
Bartolomucci, Alessandro (2) | Mele, Paolo (3) | Longo, Angela (3) | Eva, Carola (3) |
Palanza, Paola (1)
NPY and its receptors are involved in vulnerability to stress, anxiety, depression and metabolic
disorders. In conditional KO Npy1rrfb mice, the Npy1r gene inactivation is restricted to
excitatory neurons of forebrain in juveniles and adults. Bertocchi et al. (2011) showed that KO
mice presented lower body weight (bw) growth, increased anxiety and CRH-IR in PVN in relation
to sex and maternal cares received. A significant reduction of Npy1r mRNA expression in limbic
areas was found only in Npy1rrfb male mice reared by high maternal (HM) care mothers
compared to controls whereas no differences were found in male mice reared by low maternal
(LM) care dams, suggesting that early maternal environment influences Npy1r mRNA expression.
In the present study, we examined behaviour and metabolism in response to a standard (STD)
or a high fat diet (HFD) 3-week regimen in KO and control mice. To achieve gene inactivation,
after birth, mice were fostered to HM (FVB/J and CD1 strain) or LM (C57BL/6J) mothers. When
limbic Npy1r gene is inactivated, KO males showed slower bw growth compared to controls but
when challenged with a HFD, only KO males reared by HM dams showed higher bw growth,
higher blood glucose level and higher level of white adipose tissue compared to controls. KO
males reared by HM dams also showed lower aggression and were less sensitive to novelty. In
female mice we did not find any differences in behaviour and metabolism but, when challenged
with reproduction, KO females reared by HM mothers showed lower reproductive success
compared to controls. These results indicate that low limbic Npy1r expression affects both
emotional and social behaviour and metabolism increasing susceptibility to behavioural and
metabolic disorders in a sex-dependent manner. Furthermore, the early maternal environment
affects Npy1r expression in the limbic system.
(1) Dept Neuroscience - Univ of Parma IT | (2) Dept Integrative Biology and Physiology - Univ of
Minnesota MN | (3) Neuroscience Inst of the Cavalieri Ottolenghi - Univ of Torino IT
Paterlini Silvia | [email protected]
EFFECT OF ADOLESCENT Δ9-THC PRETREATMENT IN THE DOSE-RESPONSE
RELATIONSHIP OF HEROIN SELF-ADMINISTRATION IN LEWIS AND FISCHER
RATS
Lecca, Daniele (1) | Scifo, Andrea (1) | Pisanu, Augusta (2) | Sil, Annesha (1) | Cadoni,
Cristina (2) | Di Chiara, Gaetano (1,2)
Adolescent exposure to cannabis has been widely hypothesized as a predisposing factor to
opiate abuse (Gateway hypothesis), but don't adequately account for the individual
vulnerability on the behavioral disorders that may be developed in adulthood, although our
previous data shown how adolescent Δ9-THC exposure differentially affects heroin
reinforcement in adult Lewis (LEW) and Fischer (F344) rats.
The aim of this study has been to investigate the role of genetic background on the escalation
of drug intake of LEW and F344 rats, early exposed to Δ9-THC, using short and long access SA
sessions, during which heroin dose was progressively increased over sessions.
Adolescent (6th PN week) LEW and F344 rats were administered with increasing doses of Δ9THC (2,4,8 mg/kg, i.p.), twice daily, for three consecutive days. In adulthood (11st PN), each
group was trained to acquire heroin SA behavior (0.025 mg/kg/48 μl, 1-h daily session), under
a Fixed Ratio-1 (FR-1: 1NP = 1 infusion) schedule of responding, then, shifted to the long access
sessions (4-h). Dose of heroin was increased (0.025, 0.050 and 0.100 mg/kg) over seven sessions
each. After extinction, rats were underwent to reinstatement by a heroin priming.
LEW-THC rats showed higher operant responding activity and intake, and greater adaptation to
the experimental settings, compared to controls group as well as to F344 rats. No differences
were observed in the F344 groups. During extinction, both strains showed a rapid fall in
responding activity and quickly extinguished operant behavior, whereas heroin priming (0.05
mg/kg, s.c.) induced greater seeking behavior only in the LEW pretreated rats.
These findings strongly confirm that adolescent exposure to Δ9-THC influences heroin
reinforcing properties in adulthood in a strain-related manner, and demonstrates how genetic
vulnerability could play a critical role in the compulsivity abuse and/or opiate addiction as
expression of behavioral diseases.
(1) University of Cagliari - Department of Biomedical Sciences- Cagliari- Italy | (2) CNR Institute of
Neuroscience-Section of Cagliari-Cagliari- Italy
Lecca Daniele | [email protected]
EXTRACELLULAR MATRIX ACCOUNTS FOR FEAR MEMORY PERSISTENCE BY
MAINTAINING STRUCTURAL CHANGES OF DENDRITIC SPINES
Pignataro, Annabella (1) | Middei, S (2) | Pagano, R (3) | Borreca, A (2) | Ammassari-Teule,
M (1,2)
In adult animals fear memory are hard to erase. Although fear responses are attenuated
following extinction, fear can re-emerge upon memory reactivation. Fear memory formation
and stabilization associate with an increase in the number and size of dendritic spines in key
brain regions for memory and emotionality such as Basolateral Amygdala (BLA) and anterior
Cingulate Cortex (aCC). A support of fear re-emergence has been identified in the partial
persistence of memory-induced structural changes in brain regions critical for fear conditioning:
fear memory reactivation after extinction associate with an increase in the proportion of large
spines suggesting that persistence of large-type dendritic spines could have a pivotal role for
memory persistence. Extracellular Matrix (ECM) is a net of macromolecules that are secreted
locally in close association with neurons. ECM components expand into the extrasynaptic space
and surround dendritic spines in the brain, suggesting a role in their stabilization. In conditions
in which chondroitin sulfate proteoglycans (CSPGS) of ECM are degraded in BLA, memory is
formed, is extinguished, but cannot be reactivated suggesting a role of CSPGS in fear extinction
regulation. Despite such behavioral evidences the neural circuit reorganization supporting
erasure of memory upon degradation of CSPGs has not yet been clarified. We investigated this
point by injecting an enzyme -chABC- that degrades CSPGs in BLA of adult mice before tone
fear conditioning followed by extinction training, and analyze dendritic spines number and
shape in BLA and aCC. We find that CSPGs degradation induces memory erasure and inhibits
the persistence of learning-induced spine large in BLA and aCC after extinction. Our data show
that degradation of CSPGs prevents memory reactivation via a post-extinction selective
restriction of large spines and point out a causal link between CSPGs degradation, memorydriven spine enlargement, and erasure of fear memory after extinction.
(1) Department of Experimental Neurology, Laboratory of Psicobiology, Santa Lucia Foundation, Rome,
Italy | (2) Institute of Cell Biology and Neurobiology National Research Council Rome Italy | (3)
Sapienza University - Rome IT
Pignataro Annabella | [email protected]
ROLE OF THE LPA1 RECEPTOR IN MOOD AND EMOTIONAL REGULATION
Moreno-Fernández, Román, D (1) | Pérez-Martín, Margarita (1) | Rosell-Valle, Cristina (1) |
Castilla-Ortega, Estela (2) | Chun, Jerold (3) | Rodríguez de Fonseca, Fernando (2) | EstivillTorrús, Guillermo (2) | Santín, Luis J (1) | Pedraza, C (1)
Depression is a debilitating psychiatric condition characterized by anhedonia and behavioural
despair among others symptoms. Despite the high prevalence and devastating impact of
depression, underlying neurobiological mechanisms of mood disorders are still not well known.
Regardless its complexity, central features of this disease can be modelled in rodents in order
to better understand the potential mechanisms underlying.
On the other hand, the lack of LPA1 receptor compromises the morphological and functional
integrity of the limbic circuit and the neurogenesis in hippocampus, induces cognitive
alterations on hippocampal-dependent tasks and dysfunctional coping of chronic stress,
provokes exaggerated endocrine responses to emotional stimuli and impairs adaptation of the
hypothalamic-pituitary-adrenal axis after chronic stress. Factors, which all have been related
with depression.
Here, we sought to establish the involvement of the LPA1 receptor in regulation of mood and
emotion. To this end, in wild-type and maLPA1-null mice active coping responses to stress were
examined using the forced swimming test (FST). To assess hedonic behaviour saccharine
preference test and female urine sniffing test were used.
Our data indicated that the absence of the LPA1 receptor significantly affected to coping
strategies. Thus, while null mice displayed less immobility than wt in FST, exhibited more
climbing and less swimming behaviour, responses that could be interpreted as an emotional
over-reaction (i.e., a panic-like response) to stress situations. Concerning hedonic behaviour,
the lack of the LPA1 receptor diminished saccharin preference and female urine sniffing time.
Overall, these data supports the role of LPA1 receptor in mood and emotional regulation.
Specially, the lack of this receptor induced emotional dysregulation and anhedonic behaviour,
a core symptom of depression.
(1) Universidad de Málaga - Instituto de Investigaciones Biomédicas de Málaga (IBIMA) - Dpto.
Psicobiología y Metodología CC. Facultad de Psicología - Málaga - Spain | (2) Instituto de Investigación
Biomédica de Málaga (IBIMA) - Hospital Regional de Málaga - Spain | (3) Dorris Neuroscience Center The Scripps Research Inst - La Jolla - USA
| [email protected] | [email protected] | [email protected] | [email protected]
| [email protected]
Pedraza Carmen | [email protected]
MOTIVATION FOR HIGH PALATABLE FOOD IN MICE LACKING CB1
RECEPTOR IN GLUTAMATERGIC NEURONS AFTER HIGH-FAT DIET
EXPOSURE AND WITHDRAWAL
Martín-García, Elena (1) | Ruiz de Azúa, I (2) | Kummer, S (1) | Domingo-Rodríguez, L (1) |
Lutz, B (2) | Maldonado, R (1)
The type 1 cannabinoid receptors (CB1) are expressed in many brain regions that control food
intake, and regulate both excitatory and inhibitory neurotransmission through presynaptic
regulation of the neurotransmitters release. CB1 receptors are present on both GABAergic and
glutamatergic axon terminals, reducing either inhibitory or excitatory neurotransmission. In
this study, we investigated the consequences of cell-type-specific deletion of the CB1 receptor,
in glutamatergic neurons, on the motivation for high palatable food in a diet-induced obesity
model. To reach this aim, we used conditional mutant mice with specific deletion of the CB1
receptor gene (referred to as Glu-CB1-KO mice, CB1 loxP/loxP; Nex-cre mice) primarily absent
in cortical glutamatergic neurons in the dorsal telencephalon, including neurons located in
neocortex, paleocortex, archicortex, hippocampal formation and cortical portions of the
amygdala. After 1 week of exposure to high-fat diet, mice were trained in operant conditioning
maintained by chocolate-flavoured pellets under fixed ratio (FR) 1 and FR5 schedule of
reinforcement. Motivation for chocolate was assessed in a first period after 3 weeks of high-fat
diet exposure and in a second period after 5 weeks of high-fat diet exposure followed by 1 week
of high-fat diet withdrawal through a progressive ratio schedule of reinforcement. Results
revealed a significant increase of motivation for chocolate-flavoured pellets in WT mice and
interestingly this effect was blunted in Glu-CB1-KO mice exposed to the same diet schedule.
Together, these results indicate that the CB1 receptor signaling on cortical excitatory neurons
controls motivation for high palatable food.
(1) Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat
Pompeu Fabra - Barcelona Spain | (2) Institute of Physiological Chemistry, University Medical Center
of the Johannes Gutenberg University Mainz, Mainz German
Martín-García Elena | [email protected]
THE EFFECT OF ALCOHOL ON THE SENSE OF AGENCY: AN INTENTIONAL
BINDING STUDY IN HEALTHY SUBJECTS
De Pirro, Silvana (1) | Parkinson, Jim (2) | Ouliel, Daniel (1) | Critchley, Hugo (1,2) | Duka,
Theodora (1) | Badiani, Aldo (1,3)
The Sense of Agency (SoA) refers to the subjective experience of voluntary control over actions.
The ‘Intentional Binding’ (IB) paradigm, which evolved from Libet’s experiments on the
neurophysiological basis of human volition, was developed to provide a proxy for the SoA
(Haggard et al. 2002, Moore & Haggard, 2008). Using a ‘Libet’s clock’ subjects report the time
of either a voluntary action (e.g., pressing a button) or the time of a sensory event (e.g.,
hearing a tone). When the voluntary action and the sensory event are coupled, humans tend to
judge their action as occurring later in time and the sensory event as occurring earlier in time,
relative to when both events occur separately, indicating the ‘binding’ of the two processes.
Recent studies have shown that pharmacological manipulations may affect the SoA. Ketamine
(a drug of abuse that acts as an NMDA receptor antagonist) has been shown to increase IB in
healthy subjects (Moore et al. 2011). Increased IB was also found in Parkinsonian patients
receiving dopaminergic medications, which can produce addiction-like behavior, (Moore et al.
2009). The aim of the present study was to investigate the effect of alcohol, the most widely
abused drug world-wide, on IB. Twenty-six healthy social drinkers (14 female; mean age = 21.2
years) received either placebo or one of two doses of ethanol: 0.4 and 0.6 g/kg of ethanol (on
average 2.5 and 4 UK alcohol units, respectively) before performing the IB task. We found that
both alcohol doses increased overall binding relative to the placebo condition, suggesting that
acute alcohol exposure can affect the SoA. These findings may have important implications in
the light of theories that conceptualize drug abuse as a disorder of will (see Pierre 2014).
Further studies are necessary to investigate the effects of other addictive drugs on the SoA.
(1) Sussex Addiction Research and Intervention Centre - School of Psychology - University of Sussex Brighton UK | (2) Sackler Centre for Consciousness - University of Sussex - Brighton UK | (3)
Department of Physiology and Pharmacology - Sapienza University of Rome - Italy
De Pirro Silvana | [email protected]
GLUCOCORTICOID INTERACTION WITH THE ENDOCANNABINOID SYSTEM
IN THE STRIATUM IN REGULATING MEMORY CONSOLIDATION
Siller Pérez, Cristina (1) | Sotelo Barrera, Erika L (1) | Serafín López, Norma (1) | PradoAlcalá, Roberto A. (1) | Campolongo, Patrizia (2) | Roozendaal, Benno (3) | Quirarte, Gina L
(1)
Glucocorticoid hormones modulate distinct types of memory acting in different brain structures.
Corticosterone administered into the dorsal striatum enhances memory consolidation of an
inhibitory avoidance task. Previous studies in the amygdala have indicated that glucocorticoids
recruit the endocannabinoid system in influencing memory consolidation. However, the role of
striatal endocannabinoids in mediating glucocorticoid effects on memory consolidation of
emotionally arousing experiences is unknown. Our objective was to investigate if
glucocorticoids and striatal endocannabinoids act in concurrence to consolidate an aversive
memory. Male Wistar rats were implanted bilaterally with cannulae into the anterodorsal
striatum and trained on an inhibitory avoidance task. First, independent groups of rats received
the CB1 receptor antagonist AM251 (0.28 or 0.56 ng/µl) or its vehicle into the striatum
immediately after training with a high foot-shock (0.6 mA, 1 s), and memory retention was
evaluated 48 hours later. Subsequently, independent groups of rats were trained with a low
foot-shock (0.45 mA, 1 s) and immediately after training they received AM251 (0.56 ng/µl) or
its vehicle into the striatum followed by a systemic administration of corticosterone (3 mg/kg
i. p.) or its vehicle; memory retention was evaluated 48 h later. We found that AM251
administration (0.56 ng/µl) produced a significant impairment in retention. The systemic
administration of corticosterone enhanced memory consolidation; importantly, this effect was
blocked by the previous intra-striatal administration of AM251 (0.56 ng/µl). Our findings provide
evidence of the interaction between endocannabinoids and glucocorticoids in the modulation
of emotional memory, suggesting that the endocannabinoid system needs to be active upstream for glucocorticoids to enhance memory consolidation of an aversive training experience.
We thank the excellent technical support from Cristina Medina, Ángel Méndez, Leonor Casanova,
Lourdes Lara. This work was supported by PAPIIT-DGAPA, UNAM IN202414, and CONACYT (Grant
130524, and scholarship 371741 to C.S.P).
(1) Departamento de Neurobiología Conductual y Cognitiva- Instituto de Neurobiología- UNAM Campus
Juriquilla- Querétaro- México.(2) Department of Physiology and Pharmacology- Sapienza University of
Rome - Rome - Italy | (3) Department of Cognitive Neuroscience - Radboud University Medical Centre and Donders Institute for Brain - Cognition and Behaviour Radboud University Nijmegen - Nijmegen The Netherlands
Siller Pérez Cristina | [email protected]
THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE SHARES DISCRIMINATIVE
STIMULUS PROPERTIES WITH SOME, BUT NOT ALL BENZAMIDE
DERIVATIVES
Donahue, Timothy J. (1) | Webster, Kevin A. (1) | Hillhouse, Todd M. (2) | Cooper, Charlotte
H. (1) | Young, Richard R. (3) | De Oliveira, Eliseu O. (4) | Porter, Joseph H. (1)
Amisulpride, a benzamide derivative, is a second generation (atypical) antipsychotic drug used
to treat both positive and negative symptoms of schizophrenia and also, at low dose, depression.
Approved in Europe, amisulpride displays an atypical clinical profile with efficacy for treating
both positive and negative symptoms of schizophrenia with reduced extrapyramidal motor
effects. It has a relatively selective binding profile that distinguishes it from most other
antipsychotic drugs, having antagonist activity at dopamine D2 and D3 receptors and at
serotonin 5-HT2B and 5-HT7 receptors. The present study compared the discriminative stimulus
properties of amisulpride to other benzamide derivatives to investigate which benzamides share
similar discriminative properties with amisulpride. Adult male C57BL/6 mice (N=14) were
trained to discriminate 10 mg/kg rac-amisulpride from vehicle in a two-lever drug
discrimination task for food reinforcement in an average of 35.7 sessions (range 6-89). The
amisulpride dose-response curve (0.078 - 20.0 mg/kg) yielded an ED50 = 0.73 mg/kg (95% CI =
0.47-1.13 mg/kg). Substitution testing with benzamide derivatives revealed that sulpiride (ED50
= 7.29 mg/kg) and the (S)-sulpiride isomer (ED50 = 9.12 mg/kg) fully substituted (> 80% Drug
Lever Responding) to the amisulpride discriminative cue. Tiapride at 40.0 mg/kg (76.41% DLR)
and raclopride at 0.10 mg/kg (62.68% DLR), but not nemonapride, zacopride, or
metoclopramide partially substituted for amisulpride’s discriminative cue. These findings
demonstrate that the atypical antipsychotic amisulpride shares discriminative stimulus
properties with some benzamide derivatives such as the antipsychotic sulpiride and the (S)sulpiride isomer. However, other benzamide derivatives either failed to substitute for
amisulpride or only partially substituted for amisulpride’s discriminative cue. These results also
demonstrate that benzamide derived compounds are a diverse group of compounds much in the
same manner that antipsychotic drugs from other chemical classes represent a very diverse
group of compounds both in terms of their therapeutic efficacy and mechanisms of action.
(1) Department of Psychology - Virginia Commonwealth University - USA | (2) Department of
Pharmacology - University of Michigan - USA | (3) Department of Medicinal Chemistry - Virginia
Commonwealth University - USA | (4) Center for Drug Discovery - Georgetown University - USA
Donahue Timothy J | [email protected]
NEUROPROTECTIVE EFFECTS OF THE NEUROSTEROID BNN-50 IN THE
NIGROSTRIATAL DOPAMINERGIC CELLS OF THE WEAVER MUTANT MOUSE
Delis, F (1) | Botsakis, K (2) | Mourtzi, T (2) | Panagiotakopoulou, V (2) | Panagopoulos, N (2) |
Angelatou, F (3) | Charalampopoulos, I (4) | Antoniou, K (1) | Gravanis, A (4) | Matsokis, N (2)
The weaver (wv/wv) mouse is a genetic model of Parkinson's disease(PD) that exhibits progressive
dopaminergic neurodegeneration in substantia nigra (SN), thus consisting an ideal animal model
for the study of neuroprotective compounds. We studied the potential neuroprotective effects of
BNN-50 (17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol) on nigrostriatal dopaminergic neurons
in wv/wv mice. BNN-50 is an analog of the neurosteroid DHEA (dehydroepiandrosterone), with the
advantage of not being metabolized to estrogens. Wild-type (+/+) and wv/wv mice received daily
i.p. injections of BNN-50 (100mg/kg) or DHEA (100mg/kg) from P1 to P21. Neuronal survival and
function of the nigrostriatal projection were estimated with the use of tyrosine hydroxylase (TH)
immunohistochemistry. Dopaminergic activity in the striatum was assessed using high pressure
liquid chromatography with electrochemical detection. Antiapoptotic effects of neurosteroid
treatments were measured with western blot for anti-apoptotic Bcl2 and pro-apoptotic Bax
proteins in midbrain and striatal tissues. DHEA and BNN-50 treatments in wv/wv mice resulted in
(i) a substantial increase in the number of TH-positive cells in the SN and (ii) an increase in the
intensity of the TH-positive immunohistochemical signal in the striatum, compared with vehicle
treated wv/wv. No effects of either neurosteroid were observed in wild-type mice. DHEA and
BNN-50 treatments in wv/wv mice led to higher Bcl2/Bax ratio in the midbrain of wv/wv mice,
compared with vehicle-treated wv/wv, which could suggest an overall anti-apoptotic effect of
these neurosteroids on SN neurons. Dopamine turnover ratio increased significantly after
neurosteroid treatments in the striatum of wv/wv mice, compared with vehicle-treated wv/wv
mice and with neurosteroid treated wild-type mice. The results show that BNN-50 increases the
viability of SN neurons and enhances striatal dopaminergic activity in the weaver animal model of
PD. Our findings suggest that BNN-50 may be a candidate compound for the treatment of PD
disease.
Acknowledgement: This work was funded by the research program Thalis, MIS: 380342; Ministry of Education,
Lifelong
Learning
and
Religious
Affairs;
European
Social
Fund;
NSRF
2007-2013.
(1) Department of Pharmacology - Faculty of Medicine - University of Ioannina - Ioannina - Greece | (2)
Laboratory of Human and Animal Physiology - Department of Biology - University of Patras - Patras - Greece
| (3) Department of Physiology - Faculty of Medicine - University of Patras - Patras - Greece | (4)
Department of Pharmacology - Faculty of Medicine - University of Crete - Heraklion - Greece
Delis Foteini | [email protected]
Monday, 14th September
CHRONIC SOCIAL INSTABILITY STRESS AND ACUTE IMMUNOSTIMULATION
HAVE A SYNERGESTIC INFLUENCE ON BDNF IN THE OFLACTORY BULBS OF
FEMALE RATS.
Nowacka, Marta (1,2) | Paul-Samojedny, Monika (3) | Kasprowska-Liśkiewicz, Daniela (2) |
Bielecka, Anna (2) | Obuchowicz, Ewa (2) | Małecki, Andrzej (1)
Olfactory bulb is one of the prominent post-developmental neurogenesis areas in the adult
mammalian brain It was suggested, that neuroinflamation as well as neurotrophic factors are
involved in the response to stress in brain. Lipopolysaccharide (LPS) is a bacterial endotoxin
and has long been considered a very potent activator of the innate immune machinery that
leads a systemic and central neurochemical and endocrine changes.
The study was carried out to investigate the influence acute immunostimulation on the
expression and the level of BDNF in olfactory bulbs of female rats subjected to chronic stress.
Adult female Sprague-week stress,
including phases of isolation and over-crowding, in an unpredictable manner. To enhance
unpredictability, rats were mingled with unfamiliar animals in each crowding phase. On the last
day of the experiment, rats being at the estrus phase were injected ip. with LPS (1 mg/kg/2ml)
or saline. Six hours later the rats were decapitated and the olfactory bulbs were immediately
isolated, and trunk blood samples were collected. QRT-PCR experiments were performed using
TaqMan Gene Expression Assays (Life Technologies, USA) with ABI PRISM 7700 Sequence
Detection System. The BDNF concentration was measured with a conventional ELISA assay
(Chemicon, Merck Millipore, USA).
Chronic social stress or LPS alone had no effect on the BDNF mRNA expression and protein levels
in the olfactory bulbs. However, the BDNF mRNA levels were remarkably lower by 87,6% in the
LPS-treated rats exposed to stress as compared to the stressed saline-treated rats (p<=0.05).
In conclusion, our results suggest that chronic stress and peripheral inflammation induce
deleterious alterations leading to the remarkable reduction of BDNF expression, which, taking
into account the importance of this trophic factor, may result in an increased damage of
neurons in olfactory bulbs.
(1) Laboratory of Molecular Biology - The Jerzy Kukuczka Academy of Physical Education - Poland | (2)
Department of Pharmacology - Medical University of Silesia - Poland | (3) Department of Medical
Genetics - Medical University of Silesia - Poland
Nowacka Marta | [email protected]
NEUROPEPTIDE S IMPROVES WORKING MEMORY BY MODULATING
PREFRONTAL CORTEX AND AMYGDALA NEURAL ACTIVITIES IN SLEEPRESTRICTED MICE
Chauveau, F (1) | Poly-Thomasson, B (1) | Granon, S (2) | Thomasson, J (1) | Canini, F (1)
Neuropeptide S (NPS) is a recently-discovered endogenous neuropeptide modulating anxiety,
stress responsiveness, waking state and cognitive functions. Previous works emphasise NPS
action in promoting short and long term memories. However, nothing is known about executive
functions such as working memeory. Otherwise, NPS improves arousal and decreases sleep time.
Again, nothing is known about NPS administration effect on working memory and its associated
neural networks after sleep restriction.
To that aim, C57-Bl/6J male mice were submitted to 20 h-sleep restriction then treated with
NPS (0.1 nmol icv) then submitted to 20-minutes later to a working memory (WM) evaluation
using the spontaneous spatial alternation task. After the behavioral testing, brains were
perfused for Fos immunohistochemistry to assess neuronal brain activation level in the dorsal
hippocampus, the prefrontal cortex and the amygdala.
Results showed that sleep restriction significantly decreased WM at long (30 s) but not short
(5s) inter-trial intervals. Sleep restriction failed to significantly modify c-fos immunopositive
cells in vehicle-injected animals. The NPS administration prevented WM deficits in sleep
restricted mice and modulated the Fos labelling in the prefrontal cortex and amygdala.
In conclusion, NPS enhanced working memory after an acute sleep restriction and modulates
the prefrontal cortex and amygdala activation.
Keywords: Neuropeptide S - working memory - sleep restriction - prefrontal cortex - amygdala
Funding source : grant to FC from DGA France (project PDH-1-SMO-2- 0504)
Ethical committee : All experiments were executed in a manner that minimized suffering and
the number of animals used,in accordance with the Directive 2010/63/UE of the European
Parliament and approved by the Institutional Animal Care and Use commitee of IRBA (project :
Chauveau11-05)
(1) IRBA Bretigny - France |(2) Neuroscience Paris-Saclay - Inst Univ Paris - France
Chauveau F | [email protected]
FACIAL MIMICRY AND THE MIRROR NEURON SYSTEM
Żurawski, Łukasz (1) | Szatkowska, Iwona (1) | Marchewka, Artur (1) | Jankowiak-Siuda,
Kamila (2) | Rymarczyk, Krystyna (1, 2)
Understanding the emotional facial expressions of others is important for daily social
functioning. It has been shown that humans react to emotional facial expressions with specific,
congruent facial muscle activity (facial mimicry). These facial muscular reactions appear to be
spontaneous and automatic. According to current literature, the neuronal base of such mimicry
is presumably the “mirror neuron system” (MNS). The current study investigated the neuronal
structures responsible for differences in the occurrence of facial mimicry reactions by
simultaneously measuring BOLD and facial EMG in an MRI scanner.
Forty-six participants (25 men) were presented with photographs and short clip video depicting
people expressing happiness or anger. Facial EMG signals from muscles responsible for frowning
(m. corrugator supercilii) and smiling (m. zygomaticus major) were measured. Participants
were instructed to passive observe emotional expressions. The Emotional Contagion Scale (ECS)
was designed to assess subjects’ susceptibility to “catching” happiness or anger. Firstly, our
study has shown that subjects react with congruent facial expressions when looking at an
emotional face, particularly happy faces increased m. zygomaticus major, decrease m.
corrugator supercilii EMG activity - showing greater changes in response to dynamic than to
static stimuli in these muscles. In contrast, angry faces evoked only small changes in the
corrugator muscle EMG. We found that dynamic in comparison to static stimuli provide wider
activation networks, mainly within MNS network. Moreover, some correlations between EC
ratings, EMG and BOLD signal were obtained. Activation of left posterior insula was found
negatively correlated with CS response for dynamic anger expression. On the other hand, EC
ratings were positively correlated with right insula activity for happy expressions. We suggest
that the insula may contribute to produce an emotionally relevant context for sensory
experience. It appears also that in some specific social situations the property of dynamicity
facilitates processing of facial expressions of emotion.
(1) Nencki Institute Of Experimental Biology - Poland |(2) University Of Social Science & Humanities Poland
Łukasz Żurawski | [email protected]
NITRIC OXIDE MAY BE IMPLICATED IN THE EXTINCTION MEMORY
FORMATION OF LITHIUM-INDUCED CONDITIONED TASTE AVERSION
Jeong Won, Jahng (1) | Vitaly, Ryu (2) | Jin Young, Kim (1) | Jong-Ho, Lee (1)
Lithium chloride is conventionally used as an unconditioned stimulus (US) in the formation of
conditioned taste aversion (CTA), a form of classical conditionings. Lithium chloride increases
both the synthesis and activity of nitric oxide synthase in the brain regions implicated in CTA
learning, and nitric oxide donors have been reported to produce a CTA in rats. This study was
conducted to examine tentative implications of nitric oxide and nicotinic receptor activation
in the acquisition and extinction of lithium-induced CTA learning. Rats were pretreated with
nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) or nicotinic
acetylcholine receptor antagonist mecamylamine either at the conditioning (sucrose-lithium
pairing) or at each drinking test. L-NAME prior to lithium chloride (US) did not affect the lithiuminduced CTA formation; however, L-NAME at a dose of 30 mg/kg prior to each sucrose
(conditioned stimulus; CS) drinking test significantly suppressed CS intake. Mecamylamine prior
to US did not affect the acquisition of lithium-induced CTA, but at high dose (2 mg/kg), it
facilitated the extinction. Mecamylamine (2 mg/kg) prior to each CS test delayed the extinction
of lithium-induced CTA memory. Results suggest that nitric oxide may be implicated in the
extinction memory formation of lithium-induced CTA, possibly in relation with the activation
of nicotinic acetylcholine receptor.
Keywords: Conditioned taste aversion, Lithium chloride, Nitric oxide
Supported by grants from the National Research Foundation (2013R1A1A3A04-006580) and the
Oromaxillofacial Dysfunction Research Center for the Elderly at Seoul National University in
Korea (2014050477) funded by the Ministry of Science, ICT and future Planning
(1) Dental Research Institute - Department of Oral & Maxillofacial Surgery - Seoul National University
School of Dentistry - Seoul - Korea | (2) Department of Biology - Georgia State University - Atlanta, GA
- USA
Jeong Won Jahng| [email protected]
FLUOXETINE EFFECTS ON MOLECULAR, CELLULAR AND BEHAVIORAL
ENDOPHENOTYPES OF DEPRESSION ARE DRIVEN BY THE QUALITY OF THE
LIVING ENVIRONMENT
Poggini, Silvia (1) | Milior, Giampaolo (2) | Alboni, Silvia (3) | Brunello, Nicoletta (3) |
Cirulli, Francesca (1) | Maggi, Laura (2) | Branchi, Igor (1)
Selective serotonin reuptake inhibitors (SSRIs) are the most common pharmacological treatment
for Major Depression. However, their efficacy is variable and incomplete. A recent hypothesis,
named the Undirected Susceptibility to Change, posits that SSRIs may not affect mood per se
but, enhancing neural plasticity, may render the individual more susceptible to the influence
of the environment. Consequently, SSRI administration in a favorable environment would lead
to a reduction of symptoms, while in stressful conditions would lead to a worse prognosis. To
evaluate this hypothesis, we treated C57BL/6 adult male mice with either fluoxetine or vehicle
while exposing them to either an enriched or a stressful condition, following a chronic stress
period aimed at inducing a depression-like phenotype. Liking- and wanting-type anhedonia,
cognitive bias, brain BDNF and circulating corticosterone levels, considered endophenotypes of
depression, were investigated. In addition, we assessed hippocampal plasticity, measuring the
long term potentiation (LTP) at Schaffer collateral-CA1 synapses. Mice treated with fluoxetine
exposed to an enriched condition improved their depression-like phenotype compared to
controls, displaying reduced anhedonia, more "optimistic" bias toward ambiguous stimuli,
higher BDNF and reduced corticosterone levels. By contrast, when chronic fluoxetine
administration occurred in a stressful condition, treated mice showed a more pronounced
worsening of the depression endophenotypes. In addition, mice showed significantly increased
LTP in the stressful but not in the enriched condition. Our findings suggest that the effects of
SSRI on the depression-like phenotype is not determined by the drug per se but is induced by
the drug and driven by the environment. These findings may be helpful to explain variable
effects of SSRI found in clinical practice and to device strategies aimed at enhancing their
efficacy by means of controlling environmental conditions.
(1) Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy. | (2)
Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, Italy.
| (3) Department of Life Sciences, University of Modena and Reggio Emilia - Modena, Italy
Poggini Silvia | [email protected]
CHRONIC EARLY-LIFE STRESS PROGRAMS STRESS-INDUCED GENE
EXPRESSION PATTERNS OF OXTR AND AVPR1A IN ADULTDOOD
Lesse, Alexandra | Rether, Kathy (1) | Gröger, Nicole (1) | Bock, Jörg (1) | Braun, Katharina
(1)
Chronic early-life stress (ELS) has been shown to be a programming factor for the development
of psychopathologies such as depression, PTSD or anxiety disorders. In animals, disturbance of
mother-child interactions such as maternal separation represents a well-established model to
induce ELS. Such early stressful experiences influence the reactivity to and coping with stress
experiences (“second hit”) at later life periods. However, the detailed mechanisms of the
second hit exposure are just poorly understood. In the present study we focus on the
oxytocinergic and the vasopressinergic system, which are known for their modulating effects
on stress sensitivity and responsiveness via the hypothalamic-pituitary-adrenal (HPA) axis.
Using an animal model that combines maternal separation (ELS) with subsequent social isolation
we aimed to test (1) if gene expression patterns of the oxytocin (Oxtr) and arginine vasopressin
receptor type 1a (Avpr1a) in the hippocampus (HC) and prefrontal cortex (PFC) are modulated
by chronic early life stress, (2) if ELS animals show increased depressive-like behavior in the
forced swim test (FST) and the sucrose preference test (SPT) in adulthood and (3) if the FST as
a second acute stressful event during adulthood (Second Hit) exhibits further effects on the
gene expression patterns of Oxtr and Avpr1a and interacts with ELS pre-experience. Our results
reveal that ELS animals showed increased depressive-like behavior, indicated by longer floating
times during the FST and less sucrose consumption (anhedonia) during the SPT.
Furthermore, gene expression analysis of Oxtr and Avpr1a in the HC and PFC revealed a
programming effect of ELS for the second-hit stress experience, since an increase of both genes
could only be observed in animals with both (first and second hit) stress experience but not in
animals with ELS alone.
(1) Department of Zoology and Developmental Neurobiology - Institute of Biology - Otto von Guericke
University Magdeburg - Magdeburg, Germany
Lesse Alexandra | [email protected]
CONSTITUTIONAL DIFFERENCES IN GLUCOCORTICOID RESPONSIVENESS
TO PERIPUBERTY STRESS ARE ASSOCIATED WITH DIFFERENCES IN
PSYCHOPATHOLOGY-LIKE BEHAVIORS IN RATS
Walker, Sophie, E (1) | Fournier, C (1) | Sandi, C (1)
We have previously shown that subjecting rats to peripuberty stress (PPS) induces long-lasting
alterations in socio-affective behaviour and that, in the social domain, glucocorticoid
production and actions can be ascribed a key role in these changes. As corticosterone levels
immediately after PPS were found to correlate with expression of dysfunctional behaviours at
adulthood, we hypothesised that individual differences in stress responsivity might represent a
differential vulnerability for the development of psychopathology following PPS. Starting from
a population of outbred Wistar rats, selective breeding of 2 lines was established according to
animals’ response to two psychogenic stressors across postnatal days 28-30. Rats expressing
extremes in plasma corticosterone values at offset of p30 stressors were selected for a 'Low-'
and 'High-' corticosterone breeding line. We evaluated socio-affective behaviours in F6 both,
following control conditions or exposure to PPS (7 days from P28 to P42). As compared to the
Low-line, animals from the High-corticosterone line spent: (I) less time on the open arms of an
elevated plus maze; (II) less time swimming in a forced-swimming test; and (III) more time
engaged in aggression during a resident-intruder test. No major effect of PPS was found in any
of these particular measurements. However, under social challenge, we found an interaction
between animals’ constitution and the impact of PPS experience on abnormal aggression toward
a conspecific. Specifically, Low-line rats exposed to PPS displayed aberrant forms of aggression
more frequently than any other group. These data indicate that animals selected to have a
constitutively high corticosterone response to repeated stress (i.e., impaired adaptation) show
enhanced anxiety- and depression-like behaviours at adulthood, as well as altered social
behaviour. The lack of additional effects of PPS exposure in these behaviours might be related
to epigenetic transgenerational effects induced during the development of the rat lines.
(1) Lab of Behavioral Genetics - Brain Mind Institute - Lausanne - Switzerland
Sophie E Walker | [email protected]
INDEPENDENT COGNITIVE MAPS OF TWO SPATIAL REFERENCE FRAMES,
THEIR MENTAL SWITCHING AND IMPAIRMENT IN SCHIZOPHRENIA
Vlček, Kamil (1) | Fajnerová, Iveta (1,2) | Rodriguez, Mabel (2) | Brom, Cyril (3) | Blahna,
Karel (1) | Levčík, David (1) | Španiel, Filip (2)
Movement of one part of an environment relative to others (like on a carousel) dissociates them
regarding orientation in space. Finding a goal in such environment requires that one selects the
relevant frame of reference (i.e. rotating or stable) and orients relative to it to estimate his/her
own position and position of the goal. We used a virtual environment with a rotating platform
dissociating the reference frames (RFs) of the room and the platform to study the associated
spatial cognitive maps in human and their impairment in schizophrenia patients. The subjects
should point at hidden goals in either room or platform reference frame upon showing their
name on a screen and then reach them by walking. The time to point to a hidden goal seems
to be strongly influenced by the RF of previous goal: changing the goal RF was associated with
a longer pointing time. This switch cost results from the processes of activation of the spatial
representation of relevant RF, followed by reorientation in this frame. The presented study
explored the hypothesis that mental spatial representations of two dissociated RF are
independent and not accessible simultaneously and focused also on separation of these
representations in schizophrenia. This psychiatric disease has been associated with cognitive
symptoms, besides others with the deficits in cognitive flexibility and in the ability to
distinguish the relevant from irrelevant information. These deficits present also as an
impairment in reference frames switching. The study was supported by IGA MZ CR grant
NT13386.
(1) Institute of Physiology - Czech Republic | (2) National Institute of Mental Health (NIMH) Klecany Czech Republic | (3) Faculty of Mathematics and Physics Charles University - Czech Republic
Vlček Kamil | [email protected]
THE NON-SELECTIVE CANNABINOID RECEPTOR AGONIST, WIN55,212-2,
ATTENUATED ACTIVATION OF THE IMMUNE SYSTEM AND MONOCYTE
TRAFFICKING TO THE BRAIN INDUCED BY REPEATED SOCIAL DEFEAT
STRESS IN MICE
Sabrina, F, Lisboa (1,2) | Daniel, Shea (2) | Francisco, Guimarães (1) | Jonathan, P, Godbout
(2,3,4) | John, F, Sheridan (2,3,5)
Repeated social defeat (RSD) is a model of social stress that promotes microglia activation,
myeloid cell trafficking, and prolonged anxiety-like behavior. Pharmacological agents that
target cells of both the peripheral and central immune system may be beneficial in the
treatment of stress-related disorders, especially stressors that promote a pro-inflammatory
response. Several lines of evidence indicate that the induction of the cannabinoid system
dose-dependently attenuates behavioural effects of stress. While cannabinoids have several
effects within the central nervous system, they can have potent anti-inflammatory effects on
innate immune cells including monocytes, macrophages and microglia. Therefore, the purpose
of this study was to determine the degree to which treatment with a cannabinoid agonist during
RSD attenuated neuroinflammation and trafficking of myeloid cells to the brain. To address this
objective, C57BL/6 mice were injected i.p. with a non-selective cannabinoid agonist,
WIN55,212-2, 30 minutes prior to each of the six exposures to social defeat. Samples were
collected 14 h after the last exposure to social defeat. Here we show that RSD-induced
myelopoiesis and the release of inflammatory monocytes (CD11b+/Ly6Chi) into circulation were
decreased by systemic cannabinoid activation. Moreover, the administration of the cannabinoid
agonist also limited RSD-induced splenomegaly with reduced accumulation of granulocytes in
the spleen. Furthermore, RSD-induced trafficking of inflammatory monocytes to the brain was
blocked by the cannabinoid agonist. These reduced immune effects of the cannabinoid agonist
were associated with a reversal of RSD-induced anxiety. Collectively, these results indicate that
intervention with a cannabinoid agonist during repeated social defeat attenuated the activation
of immune system and reduced the corresponding enhancement of neuroinflammation that
influences behaviour.
(1) Pharmacology Department - Medical School of Ribeirao Preto - University of São Paulo - Brazil (2)
Institute for Behavioral Medicine Research | (3) Center for Brain and Spinal Cord Repair (4)
Department of Neuroscience | (5) Division of Oral Biology - The Ohio State University - Columbus –
Ohio USA
Sabrina Lisboa | [email protected]
DISEASE MODIFICATION STRATEGIES FOR ALZHEIMER'S DISEASE:
SEARCHING THROUGH NATURE'S ARSENAL FOR POTENTIAL INHIBITORS
Anthony, Tsarbopoulos (1,2) | Nikolaos, Koulakiotis (1) | Dimitrios, Anagnostopoulos (1) |
Evangelia, Karkoula (2) | Ioanna Chalatsa (2) | Despina Sanoudou (2)
Neurodegenerative disorders such as Alzheimer’s Disease (AD) and Parkinson’s Disease are
persistent progressive diseases and have a major health impact along with direct and indirect
medical care costs. They are associated with abnormal accumulation and aggregation of
disease-specific proteins and peptides and inclusion bodies in selected brain regions. In case of
AD, it has been proposed that the beta amyloid peptide (Aβ), abnormal tau protein or probably
both play critical role in the development of the disease. To date, AD can only be confirmed
postmortem, and the Aβ peptide (Aβ1-40 and Aβ1-42), is the major proteinaceous component
found in plaques. In light of the suggested link between oxidative stress and neurodegeneration,
it is proposed that endogenous or dietary derived antioxidants may be prime candidates for
anti-aggregation compounds preventing aggregation of Aβ and/or promoting clearance of Aβ
aggregates.
In this study, we present an integrated approach towards the evaluation of the
antiamyloidogenic activity of isolated components from the stigmas of saffron (Crocus sativus
L.). The major Crocus sativus L.-derived components are trans-crocin-4 (TC-4) and trans-crocin3 and 2 (TC-3, TC-2), and other crocetin mono- and bis-ester glycoside compounds. These
compounds were screened for binding with Aβ employing nano-electrospray ionization (ESI)
mass spectrometry (MS), where the formation of 1:1 noncovalent complexes of Aβ with TC-2,
TC-3 and TC-4 was observed. The signals of the corresponding complexes showed considerable
stability as shown by ESI tandem MS studies. Finally, in vitro screening was supplemented with
cell viability assays using differentiated neuronal SH-SY5Y cells. At the cellular level, transcrocetin and TC-4 did not appear to have any toxic effects at concentrations up to 10μM at both
24 and 72 hours. Moreover, trans-crocetin and TC-4 appear to modestly enhance cell
proliferation at 24 hours of incubation with concentrations between 0.1 and 10 μM.
(1) Goulandris Natural History Museum - Kifissia GR | (2) University of Athens Medical School - Dep
Pharmacology - Athens GR
Anthony Tsarbopoulos | [email protected]
IN VIVO TWO PHOTON CA2+ -IMAGING DURING SLEEP IN MICE
Niels, Niethard (1) | Sato, Takashi, R (2) | Born, Jan (1,2)
The last decade has provided ample evidence that slow wave sleep (SWS) is essential for
memory consolidation. However, a definite function of rapid eye movement (REM) sleep has so
far eluded scientific scrutiny. Recently, it was shown that hippocampal pyramidal cells and
interneurons show specific firing patterns depending on the ongoing sleep stage, which
indicates competitive processes of local potentiation and global downscaling. To test if similar
firing patterns can be found in the cortex we investigated how the activity of cortical
interneurons and putative cortical pyramidal cells is organized during the different sleep stages.
Using in vivo two-photon Ca2+ imaging in transgenic mice (C57BL/6J, PV-Cre) with
labeled parvalbumin (PV) interneurons, we found that these interneurons showed decreased
firing rates during SWS, but increased firing rates during REM sleep. During SWS, firing rates of
putative pyramidal cells in the same imaging area similarly showed decreased firing rates.
During REM sleep, however, even lower firing rates of these cells were evident. Surprisingly,
the respective firing patterns of PV interneurons and putative pyramidal cells showed a similar
development within REM sleep episodes (i.e., maximum activity in the middle of the segment),
which suggests that the reduced firing rate of putative pyramidal cells during REM sleep is not
related to the increase in inhibitory activity of the PV interneurons. Interestingly, PV
interneurons showed rhythmic firing activity that was related to specific sleep pattern, which
was facilitated by their synchronous firing.
We conclude that PV interneurons play an important role for organizing cortical excitability
during sleep and that REM sleep coincides with a unique profile of neuronal activity in the
cortex, which must be considered to understand REM sleep function.
(1) Inst Medical Psychology/Behavioral Neurobiology - Univ Tübingen - DE | (2) Werner Reichardt
Center for Integrative Neuroscience - Univ Tuebingen - DE
Niels Niethard | [email protected]
THE SUBTHALAMIC NUCLEUS MODULATES HOW PROXIMAL SOCIAL
FACTORS INFLUENCE COCAINE CONSUMPTION IN RATS
Baunez, Christelle (1) | Giorla, Elodie (1) | Davranche, Karen (2) | Manrique, Christine (3) |
Huguet, Pascal (2) | Pelloux, Yann (1)
Although it is a truism that drug addiction often develops in a social context, proximal social
factors (i.e those surrounding the drug exposure, such as the presence of a peer) have not
received much attention in neurosciences. It is only recently that animal studies have started
taking them into account. However, they have not yet analysed their neurobiological basis.
Assuming that the brain structures involved in these processes would be those known for
influencing emotions and motivation, we have here decided to focus our interest on the
subthalamic nucleus (STN), a brain structure which lesion reduces affective responses and
motivation for cocaine. To determine whether proximal social factors interact with the STN,
we have developed a self-administration task in which rats with or without bilateral STN
excitotoxic lesions could take cocaine, while a peer (familiar or stranger) observed them.
In the presence of a peer, cocaine intake was decreased in the control group. STN lesions
further enhanced this effect. In both groups (control and lesioned), the decrease in cocaine
intake was stronger when the peer was a stranger.
These results suggest that the STN, in addition to be one of the key structures for cocaine
addiction, is involved in the neurobiological basis of how proximal social factors influence drug
addiction. This interaction resulting in a dramatic decrease in drug consumption makes the STN
even more interesting as a therapeutic target for drug addiction.
(1) Institut de Neurosciences de la Timone UMR7289 CNRS & Aix-Marseille Université Marseille France
(2) Laboratoire de Psychologie Cognitive UMR7290 CNRS & Aix-Marseille Université Marseille France
(3) Plateau technique Histologie UMR7292 CNRS & Aix-Marseille Université Marseille - France
Baunez Christelle | [email protected]
n
SIGMA1 RECEPTOR LIGANDS MAY POTENTIATE BEHAVIORAL EFFECTS OF
5ALPHA-REDUCTASE BLOCK
Kalinina, Tatiana, S (1) | Shimshirt, Alexander, A (1)
Some in vitro experiments suggest the possible involvement of σ1 receptor in neurosteroid
synthesis. The aim of the study was to investigate the behavioral effects of σ1 receptor ligands
afobazole (1 mg/kg, intraperitoneally) and fluvoxamine (25 mg/kg, intraperitoneally) in open
field test in male inbred Balb/c mice exposed to unpredictable chronic mild stress (UCMS)
and/or 5alpha-reductase blocking. In non-stressed mice, 5alpha-reductase blocker finasteride
(15 mg/kg, intraperitoneally) decreased the open field behavior by 47% compared with salinetreaded animals due to the rearing and horizontal locomotion without changing of
central/peripheral activities ratio. Afobazole or pregnenolone (20 mg/kg, intraperitoneally)
both increased explorative responses by 32% or 48%, respectively. Combined injection with
finasteride and pregnenolone in anxiolytic dose produced inhibition of explorative responses by
69% compared with finasteride only and loosened the locomotion, rearing and hole-board
exploration. Co-administration with finasteride and afobazole (0.5; 1 mg/kg) dose-dependently
decreased behavioral activity by 63% compared with finasteride attenuating the locomotion
and rearing. Mice exposed to UCM demonstrated the decrease of the activity in the central part
of the open field (18.5% in non-stressed vs 1.9% in stressed mice, p≤0.01). Fluvoxamine or
afobazole did not correct the explorative responses that have been violated by the UCMS
procedure. Acute injection with finasteride (15 mg/kg) in UCMS-treated mice produced the
increase of horizontal activity and rearing by 30% as statistical tendency ( p≥0.01 compared to
saline) without influence on the anxiety responses. Co-administration of finasteride with
afobazole or fluvoxamine produced further increase of explorative behavior with anxiolytic
component expressed as increase ratio of central/peripheral activity (14% in stressed mice
treaded with combination of substances vs 3.5% in stressed mice injected with finasteride only).
The results suggest that σ1 receptor ligands may potentiate the behavioral effects of 5alphareductase blocking. The study was supported by grant RFFI №13-04-1596
(1) Zakusov State Inst Pharmacology - Russian Federation
Kalinina Tatiana S | [email protected]
DIFFERENTIAL EFFECTS OF DOPAMINE, NOREPINEPHRINE AND SEROTONIN
TRANSPORT BLOCKERS ON EFFORT-BASED DECISION MAKING:
IMPLICATIONS FOR TREATMENT OF EFFORT-RELATED MOTIVATIONAL
SYMPTOMS IN PSYCHOPHATHOLOGY.
Salamone, John (1) | Yohn, Samantha E. (1) | Errante, Emily E. (1) | Gogoj, Augustyna (1) |
Rowland, Margaret A. (1) | Wilson, Bridget (1) | Jones, Myles (1) | Lopez-Cruz, Laura (1,2) |
Correa, Merce (1,2)
Deficits in behavioral activation, exertion of effort, and psychomotor/motivational functions
are common in people with depression and other disorders. Depressed people show a bias
towards selection of low effort activities in tests of effort-related decision making. Animal tests
of effort-related processes are being developed as models of motivational dysfunctions seen in
psychopathology. Clinical studies show that catecholamine uptake inhibition may be a useful
strategy for treatment of motivational dysfunction, thus the present research assessed the
effects of various monoamine uptake inhibitors using tests of effort-related choice. For one
group of studies, the VMAT-2 inhibitor tetrabenazine, which induces depressive symptoms in
people, was used to alter effort-related choice in rats tested on a concurrent fixed ratio 5/chow
feeding choice procedure. Tetrabenazine shifted choice behavior, decreasing lever pressing but
increasing chow intake. These effects of tetrabenazine were reversed by the catecholamine
uptake inhibitors bupropion and methylphenidate, and the selective dopamine (DA) uptake
inhibitor GBR 12909, but not by the SSRI fluoxetine or the norepinephrine uptake inhibitor
desipramine. Drugs also were assessed for their ability to increase work output in rats tested
on a concurrent progressive ratio (PROG)/chow feeding choice procedure. With this task, rats
choose between working for a preferred food (high carbohydrate pellets) by lever pressing on
a PROG schedule vs. obtaining a less preferred freely lab chow. Bupropion and GBR 12909
increased PROG lever pressing output, but fluoxetine and desipramine did not. GBR12909 also
increased PROG output after 7 days of repeated daily administration. Thus, blockade of DA
transport increases selection of the high effort activity, while inhibition of serotonin or
norepinephrine uptake do not. These results are consistent with the hypothesis that there is an
important dopaminergic component of effort-related motivational dysfunctions, and that drugs
that enhance DA transmission may be effective at treating these motivational symptoms in
humans.
(1) Department of Psychology - University of Connecticut - Storrs - CT - USA | (2) Department of
Psychobiology - Universitat Jaume I - Castello - Spain
Salamone John | [email protected]
ORAL JPC-077, A SELECTIVE VMAT2 INHIBITOR, DECREASES
METHAMPHETAMINE SELF-ADMINISTRATION AND REINSTATEMENT,
WITHOUT TOLERANCE
Arlington, G, Wilson (1) | Na-Ra, Lee (1) | Justin, Nickell (1) | John, P, Culver (1) | Peter, A,
Crooks (2) | Venumadhav, Janganati (2) | Guangrong, Zheng (2) | Linda, P, Dwoskin (1) |
Michael, T Bardo (1)
JPC-077, a 1,4-diphenethylpiperidine analog of lobelane (defunctionalized analog of lobeline),
may aid in reducing methamphetamine (METH) abuse by selectively inhibiting the effect of
METH at the vesicular monoamine transporter-2 (VMAT-2). JPC-077 was tested across three
separate experiments, each using adult male rats that were surgically implanted with jugular
catheters, from which METH infusions (0.05 mg/kg) could be earned via lever pressing in an
operant chamber.
In the first study, METH self-administering rats were gavaged with ascending doses (30-300
mg/kg, oral) of JPC-077 15-min before a test session. A >50% reduction in METH responding was
obtained when JPC-077 (100 mg/kg) was administered; importantly, this dose did not alter
food-reinforced responding in a separate group of rats nor did it reduce saline-paired locomotor
activity. In the next study, METH self-administering rats underwent 10 extinction sessions, and
then received METH (0.5 mg/kg, i.p.) immediately before the session to assess reinstatement.
JPC-077 (100 mg/kg, oral) produced a >50% reduction in reinstatement. Finally, METH selfadministering rats received either JPC-077 (100 mg/kg, oral) or vehicle for seven consecutive
sessions. Compared to the group given vehicle, the group given JPC-077 showed a significant
reduction in METH-seeking behavior during all seven sessions, but returned to baseline
performance after JPC-077 treatment was terminated, indicating that tolerance did not
develop. Together, these results suggest that the novel, orally-bioavailable compound, JPC077, is a new lead for the treatment of METH abuse.
(1) University of Kentucky - USA | (2) University of Arkansas for Medical Science - USA
Arlington G Wilson | [email protected]
EMOTIONAL EXPERIENCE IS AMPLIFIED BY AUDITORY-VISUAL FEARFUL
STIMULI IN NEAR SPACE
Taffou, Marine (1,2) | Ondřej, Jan (3) | O'Sullivan, Carol (3) | Warusfel, Olivier (1) | Dubal,
Stéphanie (2) | Viaud-Delmon, Isabelle (1)
Affective events often convey emotional information through multiple senses. Yet, little is
known about how the emotional experience elicited in the perceiver is influenced by
multisensory events.
Given the close links between space and multisensory processes on one hand and space and
emotion on the other hand, we hypothesized that the spatial location of a fearful event
interacts with the sensory channel of presentation to influence emotional experience. Whether
the event is within or outside the peri-personal space, i.e. the space near the body, could have
a role in the elicited negative emotional experience.
Two groups of participants (crowd-fearful and non-fearful) navigated in a virtual environment
modeled after Trinity College Dublin, containing crowd stimuli presented through the auditory
channel, the visual channel or both. They reported the discomfort they experienced, using
Subjective Units of Distress, as the crowds were located at close (2m) or far (8m) distances
from them. We compared the discomfort reported for unimodal (visual or auditory) and bimodal
(auditory-visual) crowd stimuli as a function of their location.
Crowd-fearful participants reported more intense discomfort in response to bimodal auditoryvisual crowds compared to unimodal crowds. This effect selectively occurred when the crowds
were located at a close, not at a far, distance from participants. These results suggest that,
spatial and multisensory characteristics of affective events combine to induce and modulate
emotional experience.
(1) STMS Lab - CNRS IRCAM UPMC- France (2) SAN Lab - Inserm CNRS UPMC ICM- France | (3) School of
Computer Science and Statistics - Trinity College Dublin - Ireland
Taffou Marine | [email protected]
BRAIN INFLAMMATION MAY CAUSE IMPAIRMENTS IN NOVEL OBJECT
RECOGNITION FOLLOWING NANOPARTICLES ADMINISTRATION.
Salvetti, Beatrice (1) | Becchi, Serena (1) | Pellitteri, Michele (1) | Perbellini, Luigi (2) |
Cerpelloni, Marzia (2) | Merigo, Flavia (1) | Benati, Donatella (1) | Osculati, Francesco (1) |
Bertini, Giuseppe (1) | Fabene, Paolo (1)
Quantum Dots (QDs) are nanoparticles composed of a heavy metal core, that are gaining
increasing attention because of their potential applications in biomedical research and
neuroscience in particular. However, little is known about their potential toxicity. Studies of
QDs biodistribution show that they accumulate in various organs, including the brain. We
hypothesized that such accumulation may elicit a systemic inflammatory response leading to
alterations in proinflammatory and signalling molecule expression in the brain. In turn, this may
lead to alterations in neuronal electrical activity, also affecting behaviour and cognitive
functions.
Following a single injection of CdTe QDs in mice we assessed: 1) accumulation of QDs in
different tissues; 2) levels of pro-inflammatory molecules (IFN-γ, TNF-α, IL-1β, Th17 and VEGF)
in the organs; 3) brain electrical activity changes; 4) behavioural alterations through the use of
a Novel Object Recognition task (NOR); locomotor impairments were excluded by performing
the Rotarod and Grip Strength Meter tests. All tests were repeated at different time points over
three weeks after the initial QDs injection.
Our findings evidenced a long-lasting accumulation of QDs in the brain, as showed by both TEM
and ICP-MS techniques. Moreover, alterations in IL-1β and IFN-γ levels were observed. The NOR
test showed memory impairments three weeks after QDs injection, with treated mice exploring
equally the novel and the familiar object.
The results show that QDs are capable to cross the BBB and reach the brain parenchyma,
accumulating in the cells for at least 3 weeks. Moreover, nanoparticles accumulating in the
tissues may cause a systemic inflammation, which is likely to alter neuronal excitability and
may underlie cognitive impairments.
The use of nanoparticles in humans remains critical. Apart from the particular characteristic of
QDs and their constituents, our data demonstrate that nanoparticles uptake can be
accompanied by behavioural impairments and inflammatory activity.
of Public Health and Community Medicine - University of Verona - Italy
[email protected] | [email protected] | giuseppe.bertini@univr.
Salvetti Beatrice | [email protected]
BEHAVIOURAL AND HYPERTHERMIC PROFILE OF 3,4-METHYLENEDIOXYN-METHYLCATHINONE (METHYLONE) IN RATS
Štefková, Kristýna (1) | Horsley, Rachel (1) | Lhotková, Eva (1) | Kadeřábek, Lukáš (1) |
Páleníček, Tomáš (1)
3,4-methylendioxy-N-methyllcathinone (methylone), belongs to a new generation of designer
phenethylamines used recreationally as "legal highs". Methylone has increased in popularity in
recent years and is aggressively marketed as an alternative to methylendioxymethamphetamine
(MDMA; ‘ecstasy’) or methamphetamine. Already, there have been fatalities due to methylone
caused by hyperthermia, serotonin syndrome and multi-organ system failure. Despite this,
psychopharmacological data remain scarce. Therefore, the present research focused on the
effect of subcutaneous methylone (5mg/kg, 10mg/kg and 20 mg/kg) in the Wistar rat (n=10)
across three behavioural procedures.
To ascertain stimulatory, psychomimetic and hyperthermic effects, we measured locomotion,
prepulse inhibition (PPI) and body temperature, respectively. To simulate effects of crowded
conditions body temperature was monitored in rats housed in groups (versus individually). Data
were analysed using factorial Analysis of Variance and independent t-tests.
Methylone increased locomotion dose-dependently and PPI was decreased only slightly. The
hyperthermic response was increased under methylone and was more extensive under crowded
conditions. These data indicate that methylone has psychopharmacological and hyperthermic
effects similar to stimulants. Our findings have implications for clinical care.
This publication was supported by the project "National Institute of Mental Health (NIMH - CZ)",
grant number ED2.1.00/03.0078 and the European Regional Development Fund and grant
VG20122015075
(1) National Institute of Mental Health - Czech Republic
Štefková Kristýna | [email protected]
INDIVIDUAL VARIABILITY OF MICRORNAS IN THE PREFRONTAL CORTEX OF
AN ANIMAL MODEL OF POST-TRAUMATIC STRESS DISORDER
Rajendran, Samyutha (1,2) | Reetu Ramesh Daswani (1) (2) | Del Vecchio, Giorgia (1) |
Presutti, Carlo (1) | Mele, Andrea (1,2) | Mannironi, Cecilia (3) | Rinaldi, Arianna (1,2)
Traumatic stress experienced during adulthood can increase in some individuals the
vulnerability to develop a long-term anxiety disorder known as post-traumatic stress disorder
(PTSD). It is well documented that stress induces plastic changes in the brain differentially
between PTSD susceptible and resilient individuals. However, the molecular bases of such
differential alterations are still unknown. In this study, we have examined the expression of
miRNAs, the key modulators of gene expression, in the mouse prefrontal cortex in the predatorexposure model of PTSD, with the aim to identify miRNAs potentially involved in the individual
response to traumatic stress. Similar to the individual variability seen in human population in
the development of PTSD, we observed variable levels of long-term anxiety in stressed mice.
This allowed us to further divide the animals in "extremely-anxious" and "non-anxious" groups.
Our preliminary data from microarray analysis suggest that several miRNAs could have a
potential role in developing vulnerability towards long-term anxiety after exposure to a trauma.
Indeed, we found several miRNAs specifically up-regulated in condition of extreme anxiety
following predator stress exposure. Interestingly, we also observed that the expression of other
miRNAs, in particular miR-144 and miR-451, were down- regulated in the non-anxious animals
compared to the extremely-anxious animals regardless of the previous stress exposure,
suggesting a possible role of these miRNAs in maintaining stress resilience in these mice. By
performing bioinformatics analysis of the altered miRNAs, we have identified several candidate
target genes, which are predominantly involved in neuronal plasticity, apoptosis, development
and miRNA regulation. Ongoing studies in the lab are aimed at validating the microarray and
characterising the functional role of selected varied miRNAs.
(1) Dept. of Biology and Biotechnology "Charles Darwin" and Centre for Research in Neurobiology
“Daniel Bovet” - Sapienza University of Rome - Italy | (2) CNR- Institute of Cell Biology and
Neurobiology-Rome-Italy | (3) CNR‐ Biology and Molecular Pathology Institute, Rome - Italy
Rajendran Samyutha | [email protected]
NEURAL SUBSTRATES OF CONDITIONED SUPPRESSION OF FOOD SEEKING
BY OPIATE WITHDRAWAL MEMORY: CONTEXT VERSUS CS
DIFFERENTIATION USING CATFISH
Le Moine, Catherine | Bonneau, Nicolas | Fournier, Marie-Line | Noé, Emilie | CailléGarnier, Stéphanie | Cador, Martine
Opiate withdrawal induces an early aversive state which can be associated to contexts and CS
and upon re-exposure might by themselves precipitate relapse. We have previously shown that
specific limbic structures subserve retrieval of opiate withdrawal memory in the conditioned
place aversion paradigm. Here we used the conditioned suppression paradigm to investigate at
behavioral and cellular levels how withdrawal aversive memories alter operant responses for
food and how these limbic structures are involved.
Ad libitum rats were trained to press a lever to gain food pellets in operant cages and then
rendered opiate dependent using subcutaneous morphine-pellets (2x75mg). During conditioning,
following a step of basal responding (context), opiate withdrawal (precipitated by naloxone
15µg/kg) was repeatedly associated with light conditioned stimuli (CS) over 6 days. On test day,
animals were presented with the withdrawal-associated context and CS and lever pressing for
food recorded. Animals were sacrificed after the session for analysis of arc mRNA expression
using catFISH to differentiate context versus CS responses.
Reactivation of the memory of the negative affective state of withdrawal suppresses active
lever pressing, and this conditioned suppression is generalized to the context. These behavioral
responses are associated with differential arc mRNA activations related to context and CS within
the PFC, NAC) BLA and HPC. Interestingly, the NAC shell is reactive to both context and CSassociated withdrawal memories with partially different neuronal populations, whereas the
NAC core is reactive only to CS. Since amygdala and hippocampus may mediate CS-US and
context-US associations respectively, we have also analyzed BLA and HPC responses. We show
that BLA activation is specific to the CS, and preliminary data also suggest that the hippocampus
(HPC), especially dorsal CA3 may be more responsive to the context. These data support the
differential role of these areas on CS vs context-induced reinstatement of operant behaviors.
Univ. Bordeaux - CNRS UMR 5287 - France
Le Moine Catherine | [email protected]
DAILY ANXIETY STATE INFLUENCE AMOUNT OF SPONTANEOUS RUNNING
DISTANCE IN RATS
Shinya Yanagita (1) | Natsuko Kubota (1) | Yurika Takano (1) | Ken Takeda (1)
Daily amount of physical activity is an important factor to confer the physiological and
psychological health benefits. Spontaneous wheel running is a common physical exercise model
in order to enhance physiological and psychological health in rodents. It is well known that daily
spontaneous wheel running distance gradually increases over several weeks from the starting
day of running. We have investigated a novel methodological target to increase physical activity
in these rat models. As the results of these studies, we found that these are close relationship
between daily low levels of spontaneous running distance and brain serotonin levels. In this
study, we examine the relationships between daily amount of spontaneous running distance
and anxiety state which is regulated by brain serotonin levels. Male Wistar rats were housed
individually in cages with or without an attached running wheel and were randomly assigned to
either physically active or sedentary conditions. Physically active rats were allowed voluntary
access to their wheels for 4 weeks. The rats were screened into high runner or low runner based
on the calculated daily running distance. We assessed the levels of brain monoamine using HPLC.
Another rats performed anxiety-like behavioral tests, such as open field and elevated plus maze
test after 4 weeks spontaneous running sessions. The results present study showed that low
runners indicate high level of brain serotonin and low anxiety state compared to high runners.
These results suggest that daily anxiety state influences daily amount of spontaneous running
distance, and that anxiolytic property may be one of the important factor to increase physical
activity.
(1) Tokyo University of Science - Japan
[email protected]
Shinya Yanagita | [email protected]
DEEP BRAIN STIMULATION OF THE VENTRAL STRIATUM ATTENUATES
AVOIDANCE BUT NOT APPROACH BEHAVIORS IN A NOVEL OBSESSIVECOMPULSIVE DISORDER TASK IN RATS
BANASIKOWSKI, T. J. (1) | GRACE A. A. (1)
Approximately two-thirds of people with obsessive-compulsive disorder (OCD) exhibit
compulsions that are performed to protect them from negative consequences, even though they
know the fear is irrational. Such avoidance behaviors rely on environmental triggers linked to
aberrant orbitofrontocortical-limbic-basal-ganglia-circuitry. Recently, deep brain stimulation
(DBS) of the ventral striatum (VS) reduced refractory OCD symptoms in patients while increasing
the effectiveness of "exposure with response prevention (EX-RP)". Using a novel model of OCDlike behavior we hypothesized that DBS of VS during EX-RP will strengthen the reevaluation of
no longer salient events, and by recording local field potentials from orbitofrontocorticallimbic-basal-ganglia regions we examined how coordinated network activity is affected
following EX-RP and DBS treatments.
Rats were trained to lever-press for food and avoid a shock predicted by a tone. The shock
could be avoided if a rat stepped on a safety platform located opposite from the sucrosedelivering lever. During EX-RP training, the platform was present but obstructed by clear
Plexiglas barrier and the tones were no longer punished with a shock (stimulus devaluation).
On the test day, rats again had access to the platform to examine if tones continued to elicit
avoidance behavior (now compulsive).
Bilateral DBS stimulation of VS during EX-RP significantly enhanced devaluation of avoidancetriggering stimulus compared to non-stimulated animals. The decrease in avoidance following
EX-RP was not associated with changes in approach behaviors as demonstrated by lack of
significant difference in lever-press suppression ratios between DBS and non-stimulated animals.
Our findings suggest that therapeutic effects of DBS in ventral striatum are most likely due to
a decrease in avoidance behaviors and not due to an increase in approach behaviors. LFP
findings suggest that persistent avoidance following EX-RP may be correlated with a loss of
gamma-frequency power in the orbitofrontal-cortex (OFC), as well as an increase in OFC-VS and
decrease in OFC-amygdala coherence, resulting in a loss of cortical control over amygdaladriven anxiety states.
(1) Department of Neuroscience - University of Pittsburgh - Pittsburgh - PA -USA
Banasikowski T. J. | [email protected]
ESTIMATION OF INDIVIDUAL WHEEL RUNNING ACTIVITY IN GROUP
HOUSING OF LABORATORY RATS BY AN ORIGINAL RADIO FREQUENCY
IDENTIFICATION SYSTEM
Natsuko, Kubota (1) | Shinya, Yanagita (1) | Yurika, Takano (1) | Ken, Takeda (1)
Behavioral studies on spontaneous exercise and feeding behavior have previously been
investigated in individual housing condition in order to correctly record individual activity.
However, numerous studies have suggested that individual housing influences the hypothalamic
pituitary adrenal axis activity to stress while social housing, that is natural condition for human
and rodents, can buffer the influence of stress responsiveness. For this reason, we cannot rule
out a possibility of negative influences of living alone on individual activity. In this study, we
tried to estimate individual wheel running activity in group housing of laboratory rats using
radio frequency identification (RFID) technology. RFID method allows to be improved and
extended popular human observations using a color code schema on animal’s tails or ears, and
to automatically track positional data of a large number of individual subjects over a long period
of time. Wistar rats were implanted with microchips subcutaneously providing each with a
unique identification number and group-housed in plastic cages with running wheel. Each cage
was equipped to monitor an individual animal’s access to running wheel using microchip-scale
system. Daily wheel revolutions in each cage were recorded digitally from counters attached
to the running wheel. Four weeks later, we obtained a lot of sequential data of individual access
to running wheel in group housing by RFID system. Since the sequential data of access behavior
by RFID system was similar to that by infrared camera, individual running distance in group
housing estimated to be calculated by multiplying wheel circumference by the number of
revolutions based sequential access data. The result from our original calculation showed
individual differences in daily wheel running distance per rats even in living together,
suggesting that using this RFID monitoring system facilitates to be found a new aspect of
individual activity of laboratory rats in social housing condition.
(1) Research Institute for Science and Technology - Tokyo University of Science - Chiba - Japan
[email protected]
Natsuko Kubota. | [email protected]
TRANSGENERATIONAL EFFECTS OF MATERNAL PRE-REPRODUCTIVE
ENVIRONMENTAL ENRICHMENT ON ISOLATION STRESS RESPONSES OF
OFFSPRING: GLUCOCORTICOID RECEPTORS EXPRESSION IN HIPPOCAMPUS
AND AMYGDALA
Berretta, Erica (1,2) | Pasqualini, Greta (1,2) | De Bartolo, Paola (2,3) | Laricchiuta, Daniela
(1,2) | Cutuli, Debora (1,2) | Foti, Francesca (1,2) | Gelfo, Francesca (1,4) | Caporali, Paola
(1,2) | Petrosini, Laura (1,2)
Recent evidence suggests that through multiple and complex mechanisms like environmental
continuity, special maternal care and epigenetic changes, parental life experiences can
influence neuronal and behavioral development of the offspring. Some influences could begin
already in the pre-reproductive phase acting as vulnerability/resiliency factors for future
development.
In this study we assessed the response to a chronic stress, as social isolation (pnd 21-35) of male
offspring from female Wistar rats exposed to a pre-reproductive environmental enrichment
protocol (EE, pnd 21-72).
By using the Stereo Investigator software we examined the eventual changes in the expression
of glucocorticoid receptors (GRs), in dorsal hippocampus and in amygdala, structures closely
implicated in hypothalamo-pituitary-adrenocortical axis (HPA) regulation.
The results showed an increased number of immunopositive cells for GRs both in amygdala and
in hippocampus in the rats exposed to chronic social isolation in comparison to controls reared
in standard conditions. EE exposure of mums seems exacerbate the difference between isolated
vs. control groups. Namely, in the amygdala the offspring of enriched mothers exhibited overall
a higher GRs expression in comparison to controls.
These results indicate a transgenerational effects of pre-reproductive maternal enrichment on
offspring stress system regarding activation (amygdala) and fine mechanisms of feedback and
homeostatic regulation (hippocampus).
The transgenerational effects of maternal pre-reproductive EE appears to foster functional
plasticity of the stress system to efficiently meet ongoing environmental demands.
(1) Department of Psychology - University Sapienza of Rome - Rome - Italy | (2) IRCCS Fondazione
Santa Lucia - Rome - Italy | (3) Department of Sociological and Psychopedagocical Studies – Marconi
University of Rome - Italy | (4) Department of Systemic Medicine – University of Tor Vergata – Rome Italy
Berretta Erica | [email protected]
ROLE OF CENTRAL NUCLEUS OF AMYGDALA IN CUE-INDUCED RELAPSE TO
METHAMPHETAMINE SEEKING AFTER VOLUNTARY ABSTINENCE
Venniro, Marco (1,2) | Cifani, Carlo (3) | Adhikary, Sweta (1) | Marchant, Nathan J. (1) |
Bossert, Jennifer M. (1) | Chiamulera, Cristiano (2) | Shaham, Yavin (1) | Caprioli, Daniele
(1)
Background: We recently established a new animal model of cue-induced methamphetamine
seeking after prolonged voluntary abstinence (Caprioli et al. Biol Psychiatry 2015). Here, we
studied the role of central amygdala (CeA) in this form of relapse.
Methods: We trained rats to self-administer palatable food (6 sessions, 2-h/day) and then
methamphetamine (15 sessions, 2-h/day). Next, voluntary abstinence (14 sessions) was
achieved via a discrete choice procedure between methamphetamine and palatable food (20
trials/day). We then assessed cue-induced methamphetamine seeking in extinction tests. We
first determined the effect of systemic injections of the dopamine D1-receptor antagonist
SCH39166 on cue-induced methamphetamine seeking and Fos expression in central amygdala
(CeA) and areas that project to CeA: basolateral amygdala (BLA), anterior insular cortex (AIC),
paraventricular thalamus (PVT), and ventral subiculum (vSub). Next, we determined the effect
of CeA and BLA injections of SCH39166 on cue-induced methamphetmaine seeking. Finally, we
combined the retrograde tracer cholera toxin subunit-B (CTb, injected into CeA) with Fos to
determine neuronal activation in the projection areas.
Results: Cue-induced methamphetamine seeking after voluntary abstinence increased Fos
expression in CeA, AIC, and PVT, but not in BLA and vSub; both Fos expression and drug seeking
were decreased by systemic SCH39166 injections. CeA, but not BLA, SCH39166 injections
decreased cue-induced methamphetamine seeking. Double-labeling analysis of CTb+Fos showed
that cue-induced methamphetamine-seeking was associated with selective activation of AIC
neurons that project to CeA.
Conclusions: Results demonstrate a critical role of CeA in cue-induced relapse of
methamphetamine seeking after voluntary abstinence and suggest a role of AIC projections to
CeA in this relapse.
This work was supported by NIDA/NIH.
(1) NIDA - USA | (2) University of Verona - Italy | (3) University of Camerino - Italy
Venniro Marco | [email protected]
REWARD-DRIVEN PLASTICITY OF SPATIAL PRIORITY MAPS: NOT ALL
INDIVIDUALS ARE ALIKE
Della Libera, Chiara (1) | Calletti, Riccardo (1) | Chelazzi, Leonardo (1,2) | Santandrea, Elisa
(1)
We recently unveiled that spatial priority maps can be altered via reward-based learning,
causing durable biases in the behavioral salience of specific locations. Participants first
underwent training, during which high or low monetary rewards were delivered in turn for
correct responses to a visual search target that could appear in different spatial locations.
Unknown to the subjects, reward probability was biased, so that some target locations were
more frequently associated with high or respectively low reward, whereas others were equally
often associated with either reward level. Effects of training were tested by means of a
different visual search task without reward. Remarkable biases in attentional priority emerged
when multiple potential targets competed for selection, revealing a competitive advantage for
targets presented in highly rewarded locations.
In a new experiment we tested the possibility that such effects might differ across individuals,
e.g., due to differential sensitivity to reward. After replicating the main findings of our previous
study, showing increased competitive advantage for targets shown in locations associated with
greater reward, we examined the impact of individual differences on performance.
Interestingly, the lasting effects of reward on attentional priority were relatively unaffected
by the predictors considered; instead significant differences across participants emerged during
training, when rewards were available. Along training performance became better for targets
at highly rewarded locations relative to those at poorly rewarded locations, and such effect
was independently affected by two main factors: Gender, with males showing larger
modulations, and the Drive subscale of the BAS questionnaire, assessing goal pursuit persistence.
These findings clearly demonstrate that individual characteristics impact basic cognitive
mechanisms, suggesting in particular that factors such as gender and motivational personality
traits play a major role in reward processing and reward-based attentional plasticity.
(1) Department of Neurological and Movement Sciences - University of Verona - Italy | (2) Italian
Institute of Neuroscience
Della Libera Chiara | [email protected]
RAPAMYCIN BLOCKS KETAMINE ANTIDEPRESSANT LIKE EFFECT IN TASKDEPENDENT MANNER
Vales, Karel (1,2) | Holubova, Kristina (1,2) | Kleteckova, Lenka (1,2) | Skurlova, Martina
(1,2) | Stuchlik, Ales (1,2)
Ketamine exhibits antidepressant effect in the various animal models of depression. The
suggested mechanism of its action is the activation of mTOR signaling pathway. The aim of
present study is to examine the effect of ketamine in the bilateral olfactory bulbectomy (OBX),
the animal model of depression. Chosen behavioral tests assessed locomotor activity (open
field), anxiety (elevated plus maze) and cognitive functions (passive avoidance, Carousel maze
and Morris water maze) since among behavioral changes detected after olfactory bulbectomy
is hyperactivity, decreased anxiety and deficits in learning and memory.
OBX and sham controls were assigned to 4 subgroups according to the treatment they received
(ketamine 10 mg/kg, saline, ketamine 10mg/kg+1mg/kg rapamycin (mTOR inhibitor),
saline+rapamycin 1 mg/kg). At different time intervals from drug administration blood samples
were collected for analysis of phosphorylated mTOR level. The objective of the present study
was to evaluate antidepressant effect of a single ketamine injection in a variety of behavioral
tests and to investigate the role of mTOR signaling pathway in mediating its antidepressant
effect. Since antidepressant effect of ketamine was reported to last up to 7 days, all tests were
terminated within one week post-injection.
The main results of our research may be summarized as follows: 1) in behavioral tests used OBX
rats significantly differed from sham operated rats; 2) treatment used had significant effect on
depressive phenotype only - OBX animals were more responsive to the treatment, 3) rapamycin
blocked the effect of ketamine in task-dependent manner and 4) intensity of stressor (mild vs.
severe) used in the behavioral tests had opposite effect on controls and on OBX animals.
This study was supported by grants GACR P304/12/G069, P303/12/1464, IGAMZCR NT134034/2012; TACR-TE01020028, RVO:67985823 and NIMH - CZ ED2.1.00/03.0078 and the European
Regional Development Fund. We would like to thank Michaela Fialova for the technical
assistance.
(1) Institute of Physiology Academy of Science - Czech Republic | (2) National Institute of Mental
Health - Czech Republic
Vales Karel | [email protected]
BASOLATERAL AMYGDALA LESION ABOLISHES MUTUAL REWARD
PREFERENCE IN RATS
Hernandez-Lallement, Julien | van Wingerden, Marijn | Schaeble, Sandra | Kalenscher,
Tobias
Pro-social choices are decisions that produce benefits for other individuals. In a recent study,
we showed that rats behaved pro-socially by choosing alternatives yielding food-access to
conspecifics. Here, we show that the basolateral amygdala nucleus (BLA) plays a crucial role in
the establishment of pro-social preferences. Rats received bilateral excitotoxic (n = 12) or sham
infusions (n = 10) targeting the BLA and were tested in a Prosocial Choice Task (PCT) where
they could decide between rewarding (“Both Reward” BR) or not rewarding a partner rat (“Own
Reward” OR). To manipulate the social context and control for secondary reinforcement sources,
rats were paired with either a partner rat (partner condition) or with an inanimate rat toy (toy
condition). Sham-operated animals exhibited a significant preference for the BR option in the
partner condition, but not in the toy condition. BLA-lesioned animals showed significantly lower
BR preference than the sham group in the partner but not in the toy condition, suggesting that
excitotoxic BLA damage impaired pro-social choice allocation. Critically, in a reward magnitude
discrimination task in the same experimental setup, both sham-operated and BLA-lesioned
animals preferred high over small rewards, suggesting that BLA lesion effects were restricted
to social contexts, leaving non-social reinforcement learning unaffected.
SUPPORT:
This work was supported by Deutsche Forschungsgemeinschaft (DFG) grant no. KA 2675/5-1 to
TK. MvW was supported by the Volkswagen Stiftung “Freigeist” fellowship, AZ 88216. The
authors declare no competing financial interests.
(1) Heinrich-Heine University Duesseldorf - Germany
[email protected]
van Wingerden Marijn | [email protected]
PISA SYNDROME IN PARKINSON'S DISEASE: AN OBSERVATIONAL
MULTICENTER ITALIAN STUDY
Tinazzi, Michele (1) | Fasano, Alfonso (2) | Geroin, Christian (1, 3) | Morgante, Francesca (4)
| Ceravolo, Roberto (5) | Rossi, Simone (6) | Thomas, Astrid (7, 8) | Fabbrini, Giovanni (9,
10) | Bentivoglio, Annarita (11) | Tamma, Filippo (12) | Cossu, Giovanni (13) | Modugno,
Nicola (10) | Zappia, Mario (14) | Volontè, Maria Antonietta (15) | Dallocchio, Carlo (16) |
Abbruzzese, Giovanni (17) | Pacchetti, Claudio (18) | Marconi, Roberto (19) | Defazio,
Giovanni (20) | Canesi, Margherita (21) | Cannas, Antonino (22) | Pisani, Antonio (23) |
Mirandola, Rina (24) | Barone, Paolo (25) | Vitale, Carmine (26, 27)
Objective: To estimate the prevalence of Pisa Syndrome (PS) in patients with Parkinson’s
disease (PD) and to assess relationships between PS and their demographic and clinical variables.
Patients and Methods: in this multicentre cross-sectional observational study, the prevalence
of PS and its relationship with the clinical features of PD patients were evaluated; the
demographic and clinical features of the patients with and without PS were then compared.
Results: A total of 1631 patients with PD entered the study. PS was detected in 143 patients
(8.8%, 95% CI 7.4-10.3%). Patients with PS were older, had lower body mass index, longer
disease duration and more severe PD, and performed worst on PDQ8 Scale. Frequent falls were
more likely to be recorded in PS group along with higher occurrence of “veering gait” (i.e. the
progressive deviation towards one side when patient walked forward and backwards with eyes
closed). Moreover, PS patients were more likely to be treated with combination of L-Dopa and
dopamine agonists and received higher daily L-Dopa dose. Finally, as for the associated medical
conditions, osteoporosis and arthrosis were significantly more frequent in patients with PS.
Multiple explanatory variable logistic regression models confirmed the association of PS with
the following variables: Hoehn & Yahr (H&Y) stage, on-going treatment with combination of LDopa and dopamine agonist, associated medical conditions and presence of “veering gait”.
Conclusions: These results suggest that PS is a relatively frequent and often disabling
complication in PD especially in the advanced stage of disease. The association is dependent of
a number of potentially relevant demographic and clinical variables.
(1) Department of Neurological and Movement Sciences - University of Verona - Verona - Italy. | (2)
Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s
Disease - Toronto Western Hospital and Division of Neurology - University of Toronto - Toronto,
Ontario - Canada. | (3) Neuromotor and Cognitive Rehabilitation Research Centre (CRRNC) - University
of Verona - Italy. | (4) Department of Clinical and Experimental Medicine - University of Messina Italy. | (5) Neurology Unit - Department of Clinical and Experimental Medicine - University of Pisa. |
(6) Department of Neurological and Neurosensorial Sciences - Neurology and Neurohysiology Unit University of Siena - Italy. | (7) Department of Neuroscience and Imaging - University of ChietiPescara. (8) Aging Research Center Ce.S.I. University Foundation - Chieti Behavioural Neurology and
Movement Disorders Unit. | (9) Department of Neurology and Psychiatry - University of Rome Sapienza
- Rome - Italy (10) IRCSS Neuromed Institute - Pozzilli-Isernia - Italy. |
(11) Department of Geriatrics - Neuroscience and Orthopedics - Università Cattolica del Sacro Cuore University Hospital Agostino Gemelli - Rome - Italy | (12) Department of Neurology - "F. Miulli"
General Hospital - Acquaviva delle Fonti (BA) - Italy | (13) Department of Neurology - AOB Brotzu Cagliari - Italy. | (10) | (14) Department G.F. Ingrassia, Area of Neurosciences; University of Catania,
Italy. | (15) Neurological Department and INSPE-Institute of Experimental Neurology, University
Hospital San Raffaele, Milan, Italy | (16) Division of Neurology, Civil Hospital Voghera (PV), Italy. |
(17) Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child
Health, University of Genova, Italy | (18) U.O.C. Parkinson e Disordini del Movimento, IRCCS
Fondazione Istituto Neurologico Nazionale "C. Mondino" Pavia, Italy | (19) Neurology Unit, Ospedale
Misericordia, Grosseto, Italy | (20) Department of Basic Medical Sciences, Neuroscience and Sense
Organs, University of Bari "Aldo Moro", Italy. | (21) Parkinson Institute, Istituti Clinici di
Perfezionamento, Milan, Italy. | (22) Movement Disorders Center, Neurological Clinic, Department of
Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy | (23) Department of
Systems Medicine, University of Rome Tor Vergata and IRCCS Santa Lucia Foundation, Rome, Italy. |
(24) Research Support and Biostatistical Unit, University Hospital Verona, Italy | (25) Center for
Neurodegenerative Diseasese (CEMAND), University of Salerno, Italy | (26) Department of Motor
Sciences and Health, University of Naples “Parthenope”, Italy | (27) IDC "Hermitage-Capodimonte",
Naples, Italy
Tinazzi Michele | [email protected]
DIFFERENTIATION OF SEVERAL TYPES OF MENTAL TRANSFORMATION OF
SPATIAL INFORMATION: INSIGHTS FROM SEX DIFFERENCES APPROACH
Nguyen, Nam (1) | Brandner, Catherine (1) | Pegna, Alan (2) | Maurer, Roland (2)
The ability to process and represent spatial information requires the manipulation and
transformation of figures, forms and views. Tasks that involve mental rotation usually lead to
improved performance in males. Mental spatial transformation by rotation can be solved
through different means. One may rely on object-based spatial transformations corresponding
to the ability to rotate objects around their axes while the environmental reference frame
remains fixed. Another approach could be spatial perspective taking which is the capacity to
adopt someone else’s spatial perspective. Thus, spatial perspective taking requires rotation of
the viewer while object-based spatial transformations produces rotation of the object. Using
two experimental tasks, we assessed the amount of variance that could be explained by the
two different types of mental transformations between sexes. Forty subjects (20 woman and
20 men) were tested in the two tasks involving alternatively spatial perspective taking or
object-based spatial transformations. Preliminary results indicate that: i) participants make
significantly more errors in object-based spatial transformations than in spatial perspective
taking; ii) these errors are modulated by amplitude of the angle; iii) gender analyses of errors
rates show a significant advantage for men for object-based spatial transformations condition
while no significant difference between sexes are observed for spatial perspective taking; iv)
no significant gender difference in response times are observed across experimental conditions.
Taken together, these preliminary data suggest that the differences observed between sexes
in mental rotation could be attributed to the type of transformation used to solve the task.
(1) University of Lausanne - Switzerland | | (2) University of Geneva - Switzerland |
[email protected]
Nguyen Nam | [email protected]
MEPHEDRONE (4-METHYLMETHCATHINONE, 'MEOW'): HYPERTHERMIC AND
ACUTE BEHAVIOURAL EFFECT IN RATS
Šíchová, Klára | Horsley, Rachel | Lhotková, Eva | Kadeřábek, Lukáš | Páleníček, Tomáš
Mephedrone (4-methylmethcathinone, MEPH) is a novel recreational drug that has rapidly
increased in popularity in recent years, especially in the UK. MEPH produces similar effect to
MDMA, amphetamines or cocaine. MEPH has a potential to induce compulsive patterns of use
as well as toxicity in overdose. Here we examined effects of three subcutaneous MEPH doses
(2.5mg/kg, 5 mg/kg and 20 mg/kg) in Wistar rats.
To ascertain stimulatory, psychomimetic and hyperthermic effects, we measured locomotion,
prepulse inhibition (PPI) and body temperature, respectively. To simulate effects of crowded
conditions body temperature was monitored in rats housed in groups (versus individually). Data
were analysed using factorial Analysis of Variance and independent t-tests.
MEPH led to considerable elevation of locomotion activity, particularly at 5 mg/kg. MEPHtreated rats displayed significantly decreased PPI; here the strongest effect was observed at
the 2.5 mg/kg dose. The strongest hyperthermic response was detected approximately one
hour after MEPH application and was the most extensive in the case of 20 mg/kg and under
crowded conditions. At least in the animal model, studied synthetic cathinone, MEPH, has a
considerable locomotor stimulant effect, and may act as a psychomimetic. Furthermore, its
toxicity might be enhanced in the crowed environment and by the level of administered dose.
Our findings regarding MEPH-induced behavioural changes and its hyperthermic effects will be
important for medical practice.
The study was supported by the project „National Institute of Mental Health (NIMH - CZ)“, grant number
ED2.1.00/03.0078 and the European Regional Development Fund, grant IGA MH CR no. NT/13897 and
grant MI CR no. VG/20122015080.
(1) National Institute of Mental Health - Czech Republic
Šíchová Klára | [email protected]
SPONTANEOUS COLOR PREFERENCES IN RHESUS MACAQUES (MACACA
MULATTA)
Skalníková, P. (1,3) | Frynta, D. (1,3) | Abramjan, A. (3) | Rokyta, R. (2) | Nekovarova, T.
(1,2,3)
Colors and color-perception may play an important role in animal ethology (foraging, intra or
inter-species communication). However, trichromatic color vision is rare among mammals and
occurs only in some primates.
Humans, apes, and most of the Old World primates are trichromatic, whereas color vision
among New World primate species varies strikingly.
In our study, we focus on spontaneous color preference of rhesus macaques (Macaca mulatta).
Macaques, as well as people, have routinely trichromatic vision. We hope the results of the
study may attribute to the discussion about evolutionary advantages of trichromatic vision.
Only few studies have been done till now to study spontaneous color preference in primates.
Previous studies show a color preference in chimpanzees (Pan troglodytes) and gorillas (Gorilla
gorilla gorilla), who preferred green and blue significantly more than the red (Wells et al.,
2008). The monkeys were tested during free exploration of objects of different colors.
We tested color preferences in repeated short sessions with using color cups of ten different,
precisely defined colors. The pair of cups of different colors (color shown in pseudorandom
order) is presented to the monkey. The two presented cups both contain equal rewards (raisins
or piece of fruit). In each trial (presentation of the pair of cups) the monkey has only one choice.
We observe which cup is the preferred one.
The cups are presented in pseudo-random order either on black or white background to control
the effect of contrast on color preference.
Our preliminary results have not proved clear preference of blue and green colors over the red.
The results show variation in color preferences and slight tendency for individual preferences.
This project was supported by GAUK 1508414, Project Prvouk P34 and by the project 'National
Institute of Mental Health (NIMH-CZ)' - grant number ED2.1.00/03.0078 of the ERDF
(1) National Institute of Mental Health - Klecany - Czech Republic (2) Department of Normal Pathological and Clinical Physiology - Third Faculty of Medicine - Charles University in Prague - Prague
- Czech Republic | (3) Ecology and Ethology Research Group - Department of Zoology - Faculty of
Natural Science - Charles University in Prague - Prague - Czech Republic
Skalníková Petra | [email protected]
COCAINE-INDUCED CONDITIONED PLACE PREFERENCE AND MOTOR
ACTIVITY ARE ATTENUATED BY THE CANNABINOID CB1 RECEPTOR
ANTAGONIST RIMONABANT AND THE CB2 RECEPTOR AGONIST JWH-133
Antoniou, K. (1) | Delis, F. (1) | Polissidis, A (1,2) | Justinova, Z. (3) | Nomikos G. (4) |
Goldberg, S. (3) †
Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and
neurobiological effects of psychostimulants. Most of these studies have focused on the role of
CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the
respective role of CB2 receptors. Therefore, further studies are warranted to elucidate the
extent of CB receptor involvement in the reinforcing and stimulant effects of cocaine.The roles
of CB1 and CB2 receptors in cocaine’s rewarding and motor properties were evaluated by
assessing conditioned place preference (CPP), conditioned motor activity, and open field
activity.
The CB1 receptor antagonist rimonabant decreased the acquisition and the expression of
cocaine-induced CPP. Rimonabant inhibited cocaine conditioned motor activity when
administered during the expression of cocaine-induced CPP. Rimonabant also decreased
ambulatory and vertical activity induced by cocaine, but had no effect when administered alone.
The CB2 receptor agonist JWH-133 decreased both the acquisition and the expression of
cocaine-induced-CPP. JWH inhibited cocaine conditioned motor activity when administered
both during the acquisition and the expression of cocaine-induced CPP. JWH-133 also decreased
cocaine-induced ambulatory activity and abolished cocaine-induced vertical activity, without
having any effects when administered alone. The results show that the cannabinoid system
modulates cocaine-induced behavior via both types of cannabinoid receptors and suggest that
CB1 and CB2 receptors have a differential role in the regulation of cocaine’s rewarding and
motor effects.
(1) Department of Pharmacology - Faculty of Medicine - University of Ioannina - Greece | (2)
Laboratory of Neurodegenerative Diseases - Biomedical Research Foundation Academy of Athens Greece | (3) Preclinical Pharmacology Section - National Institute on Drug Abuse - USA | (4) Global
Clinical Science - Takeda Development Center Americas - USA | † In memoriam
Delis Foteini | [email protected]
BELIEVING OR NOT IN TREATMENT SIDE-EFFECTS: BEHAVIORAL OUTCOME
AND PERSONALITY TRAITS ASSOCIATED TO A NOCEBO EFFECT IN MOTOR
PERFORMANCE
Corsi, N. (1) | Emadi, Andani, M. (1,2) | Tinazzi, M. (1) | Fiorio, M. (1)
Behavioural evidence shows that believing in the detrimental effects of a treatment leads to a
worse motor performance (nocebo effect). Despite subject’s belief about treatment’s efficacy
being crucial for the nocebo effect, no study until now has tackled this issue.
With this study we investigated whether the persistence of belief and personality traits could
account for individual differences in the magnitude of the nocebo response.
27 volunteers were asked to perform a force task with the right index finger, and received a
visual feedback of force. After a training, participants underwent a nocebo procedure, in which
a treatment (actually inert) was applied to the right hand together with verbal instructions
about its negative effects on force. In a conditioning session, subjects were exposed to the
(fake) effects of the treatment, by means of a surreptitious reduction of the visual feedback.
Finally, in a test session, subjects received the same treatment and performed the motor task
without reduction of the feedback.
When asked to report about treatment efficacy, two different patterns could be observed: some
subjects gave higher scores in the test compared to the conditioning session (responders, N=15),
whereas other subjects did the opposite (non-responders, N=12). Results showed that
responders had a stronger nocebo effect, as evidenced by lower levels of force (p <= 0.001),
higher feeling of weakness (p <= 0.001) and higher sense of effort (p = 0.036), compared to
non-responders. Personality questionnaires revealed that responders had lower level of
optimism (p = 0.008) and self-directedness (p = 0.048), but higher anxiety trait (p = 0.008),
harm avoidance (p = 0.008) and physiological reactivity than non-responders.
These findings show that the magnitude of the nocebo response can be modulated by different
factors, such as the persistence of subject’s belief about the efficacy of the treatment and
personality traits.
of Biomedical Engineering - University of Isfahan - Iran
Corsi Nicole | [email protected]
ROLE OF NMDA RECEPTOR ANTAGONISM IN KETAMINE’S
ANTIDEPRESSANT-LIKE EFFECTS AND DISCRIMINATIVE STIMULUS
PROPERTIES IN RATS AND MICE
Porter, Joseph H. (1) | Friar, Mary A. (2) | Merritt, Christina M. (1) | Joseph, Brian L. (1) |
Popal, Haroon S. (3) | Kalinowski, Christopher W. (1) | Pandey, Ritu (1) | Loveless, Keegan
W. (1) | Webster, Kevin A. (1) | Hillhouse, Todd M. (4)
In recent years, the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist
ketamine has been demonstrated to produce both rapid and sustained antidepressant effects
in treatment-resistant patients. These findings have spurred increased interest in targeting the
glutamatergic system for treatment of major depressive disorder and currently several drugs
are in clinical trials. Two compounds, esketamine (Ketanest S®, the (S)-ketamine isomer) and
rapastinel (GLX-13) are currently in phase II clinical trials. While both compounds work at NMDA
receptors, they produce their antidepressant effects via different mechanisms. Rapastinel is a
weak partial agonist of the glycine site on the NMDA receptor; whereas, esketamine is a
noncompetitive NMDA receptor antagonist (as is ketamine), but it also inhibits dopamine
reuptake. Thus, the exact mechanisms of action responsible for ketamine’s antidepressant-like
properties remain unclear. The present study compared ketamine’s antidepressant-like
properties in the operant assay, DRL 72 sec (differential reinforcement of low rates of
responding) in both rats and mice to other NMDA antagonists and standard antidepressant drugs
(i.e. tricyclics and selective serotonin reuptake inhibitor [SSRI]). We also compared the
discriminative stimulus properties of ketamine in rats and mice in a standard two-lever drug
discrimination task to determine if it was related to ketamine’s antidepressant-like properties.
Imipramine (tricyclic) and fluoxetine (SSRI) produced antidepressant-like effects similar to
ketamine in the DRL task, but neither shared discriminative stimulus properties with ketamine.
In contrast, the more potent NMDA antagonist MK-801 shared discriminative stimulus properties
with ketamine, but did not produce an antidepressant-like profile in the DRL task. These results
demonstrated a clear dissociation between NDMA receptor antagonists in the DRL procedure,
but similar discriminative stimulus properties. Thus, antagonism of NMDA receptors may not
fully account for ketamine’s antidepressant effects for the treatment of depression and
ketamine clearly represents a unique therapeutic mechanism (although not fully understood)
distinct from traditional antidepressants.
(1) Department of Psychology - Virginia Commonwealth University - USA | (2) Department of
Psychology - American University - USA (3) Laboratory of Brain and Cognition - National Institute of
Mental Health - National Institutes of Health - USA (4) Department of Pharmacology - University of
Michigan - USA
Porter, Joseph H. | [email protected]
IDENTIFYING FUNCTIONAL ALTERATIONS IN NEURONAL ENSEMBLES
ACTIVATED DURING ACQUISITION OF OPERANT LEARNING IN RATS
Whitaker, Leslie, R (1) | McPherson, Kylie B (1) | Beidel, Jen (1) | Bossert, Jennifer M (1) |
Shaham, Yavin (1) | Hope, Bruce T (1)
Learned associations between environmental stimuli and rewards drive goal-directed learning
and motivated behavior. These associations are thought to be encoded by specific patterns of
sparsely distributed neurons called neuronal ensembles that are determined by selective
activation of reward-predictive stimuli. The question remains as to how neurons in these
ensembles are functionally altered during learning, and which of these changes encode learned
associations. The objectives of our study were to identify ensembles of neurons strongly
activated during acquisition of operant learning, and then to determine functional alterations
specific to these neuronal ensembles. Training took place over a period of 10 days. During each
training session, rats were allowed to lever press for food pellets in the self-administration
chambers for one hour. Rats formed an association between lever pressing and food reward
over the course of several days of training. Immunohistochemical analysis was performed on
days 1, 3 and 10 of training. Preliminary data show induction of Fos expression in ventral medial
prefrontal cortex and nucleus accumbens—two regions critical for the acquisition of goaldirected learning and motivated behavior. In future experiments, we will use c-fos-GFP
transgenic rats in which strong neuronal activation activates the c-fos promoter and drives
expression of GFP. Whole cell brain slice electrophysiology will then be used to assess functional
alterations in behaviorally activated GFP-labeled neuronal ensembles.
This work was supported by NIDA Intramural Research Program.
(1) NIDA, United States
Whitaker Leslie R | [email protected]
PERIPHERAL ADMINISTRATION OF LACTATE PRODUCES ANTIDEPRESSANTLIKE EFFECTS
Carrard, Anthony | Maha Elsayed (2) | Elsa Meylan (1) | Benjamin Boury-Jamot (1,2) | JeanMarie Petit (1,2) | Pierre J. Magistretti (1,2,3) | Jean-Luc Martin (1)
Growing evidence indicate that astrocytes are involved in the pathophysiology and treatment
of depression. With respect to energy metabolism, astrocytes respond to glutamatergic
activation by increasing the rate of glucose utilization and the release of lactate. In relation to
depression, studies in cultured astrocytes have revealed that SSRI antidepressants stimulate
glycogenolysis, glycolysis and lactate release. In addition to its role as a neuronal energy
substrate, recent data from our laboratory indicate that lactate increases the expression of
plasticity-related genes including BDNF, a neurotrophic factor involved in major depression and
antidepressant treatment. Together, these data suggest that, by increasing the expression of
plasticity-related genes, and particularly BDNF, lactate may produce antidepressant-like
effects. The aim of this study was to investigate the effects of peripheral administration of Llactate on depressive-like behavior. Using a L-lactate selective biosensor inserted within the
mouse hippocampus, we first showed that intraperitoneal injection of L-lactate, that raised
blood lactate concentration by 2-3 fold, induced a long-lasting increase in extracellular lactate
concentration. We next examined the effects of peripheral L-lactate administration on
depressive-like behavior. Acute intraperitoneal injection of L-lactate reduced immobility in the
forced swim test (FST), while the non-metabolized enantiomer D-lactate did not alter
immobility time. Further investigation of the antidepressant effects of L-Lactate showed that
daily injection of L-lactate for three weeks decreased, to a similar extent as desipramine, the
immobility time in the open-space forced swim test, this decreased immobility was
accompanied by increased BDNF protein levels in the hippocampus. We also examined the
chronic effects of L-lactate on corticosterone-induced depression-like behavior. We found that,
similarly to desipramine, chronic administration of L-lactate completely inhibited the increased
immobility induced by corticosterone treatment in the forced swim and tail suspension tests.
In conclusion, our data indicate that peripheral administration of L-lactate produces acute and
chronic antidepressant-like effects.
(1) Center for Psychiatric Neurosciences, Department of Psychiatry-CHUV - Prilly-Lausanne Switzerland | (2) Laboratory of Neuroenergetics and Cellular Dynamics - Brain Mind Institute - EPFL
Lausanne - Switzerland | (3) King Abdullah University of Science and Technology - Biological and
Environmental Sciences and Engineering - Thuwal - Saudi Arabia
Carrard Anthony | [email protected]
INFLUENCE OF AGE AND GENETIC BACKGROUND ON ETHANOL INTAKE IN
A MODEL OF ALCOHOL ABUSE
Cadoni, Cristina (1,3) | Corongiu, Silvia (2) | Dessì, Christian (1) | Espa, Elena (2) | Fenu,
Sandro (2,3)
Among factors contributing to individual vulnerability to drug addiction genetic background and
age of first exposure are critical ones. Increasing evidences show that genetic factors may
account for 40-70 % of the variance of substance abuse and addiction. Given that alcohol
consumption, especially as binge-drinking, among young people is becoming an alarming
phenomenon, it urges to better understand the influence of age and genetic background in the
development of alcohol dependence. To this aim, high vulnerable Lewis (LEW) and low
vulnerable Fischer 344 (F344) rats were compared with the outbred strain Sprague-Dawley (SD).
Adolescent or adult male LEW, F344 and SD rats were exposed to intermittent alcohol access
(20 %, three 24h sessions/week), for 7 (adolescents) or 11 weeks (adults). Significant
differences were obtained between strains and age groups in ethanol intake and behavioral
reactions following consumption and during abstinence days. Both adult SD and LEW, but not
F344 rats, escalated their alcohol intake over time reaching stable levels. Adolescent rats
consumed higher amounts of ethanol than adults, but while SD did increase their intake over
time, LEW and F344 kept their intake stable. LEW rats, although having a lower ethanol
consumption compared to SD rats, showed a more compulsive intake, consuming higher
amounts of ethanol during the first hour of exposure, reducing more than SD e F344 their water
intake over time. LEW rats showed since the first exposure locomotor activation and hedonic
reactions absent in the other two strains, showing higher scores of withdrawal and seeking
behavior during abstinence. The present results underscore the importance of individual
genetic background and early onset of alcohol use in progression toward abuse and development
of alcohol addiction.
Acknowledgements: This study was supported by funds from Fondazione Banco di Sardegna e
Regione Autonoma della Sardegna, LR 7/2007, bando 2010.
(1) Institute of Neuroscience - Cagliari Section - National Research Council of Italy (CNR), Cagliari Italy | (2) Department of Biomedical Science - Neuropsychopharmacology Section - University of
Cagliari - Italy | (3) Centre of Excellence Neurobiology of Dependence - University of Cagliari - Italy
Cadoni Cristina | [email protected]
OPIOID MODULATION OF RESPONSES TO SOCIAL STIMULI IN HEALTHY
ADULTS
Bershad, Anya, K (1,2) | de Wit, Harriet (2)
In addition to its classical role in mediating responses to pain, the opioid system is strongly
implicated in the regulation of social behavior. In young laboratory animals, low doses of opioid
analgesic drugs reduce responses to isolation distress and increase play behavior. However, it
is not known how opioid drugs affect responses to social stimuli in humans. Here we examined
the effects of buprenorphine, a μ-opioid partial agonist used to treat opioid dependence and
pain, on three dimensions of social processing; i) responses to simulated social rejection, ii)
attention to emotional facial expressions, and iii) subjective ratings of images with and without
social content. Healthy adults (N = 36) attended two sessions during which they received either
placebo or 0.2mg buprenorphine in randomized order, under double-blind conditions. Ninety
minutes after drug administration, they completed three behavioral tasks: i) a virtual ball-toss
game in which they were first included and then excluded by the other players; ii) an attention
task in which they were shown pairs of faces (one emotional and one neutral), while the
direction of their gazes was recorded using electrooculography, and iii) a picture-viewing task,
in which they rated standardized images with and without social content. During the ball-toss
game, buprenorphine decreased participants’ perception of and negative mood responses to
rejection. During the attention task, the drug reduced initial attention to fearful facial
expressions, without influencing attention to angry, happy, and sad faces. Finally, during the
picture-viewing task, buprenorphine increased ratings of positivity of images with social
content, without affecting ratings of nonsocial images. These results suggest that even at low
doses, opioid analgesic drugs reduce responses to some types of negative social stimuli, while
enhancing positive responses to social stimuli. This provides further support for the role of the
opioid system in mediating responses to social rejection and social reward.
(1) Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL USA
(2) Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL USA
Bershad Anya | [email protected]
EFFECTS OF INTRANASAL OXYTOCIN ON CUE-INDUCED CIGARETTE
CRAVING
Miller, Melissa A. (1) | Bershad, Anya (1, 2) | King, Andrea (1) | Lee, Rocye (1) | de Wit,
Harriet (1)
Cigarette smoking is a major health concern worldwide and a leading cause of preventable
death. Despite moderate treatment success with both pharmacological and behavioral
treatments, many smokers find it difficult to quit and relapse rates are high. One factor known
to increase smoking, especially during attempts to quit, is reactivity to smoking-related cues.
Therefore, treatments that target cue reactivity are needed to help smokers successfully
abstain. One potential candidate for reducing smoking craving is the neuropeptide oxytocin
(OT), which has been shown to have calming effects and to reduce drug self-administration in
animals. However there have been no studies examining the effect of OT on cue-induced craving
in smokers. Here, we investigated the effects of intranasal OT (20 IU) on spontaneous craving
after overnight abstinence, and following exposure to smoking-related cues in 16 daily smokers.
In this within-subjects, double-blind, placebo-controlled study, participants attended two
laboratory sessions in which they received OT or placebo, in counterbalanced order. On each
session they received two intranasal doses. They rated their cigarette craving before and after
the first dose. Then, they received a second dose and rated their craving immediately after
exposure to smoking cues (smoking-related images and an actual lit cigarette). OT significantly
reduced baseline levels of craving compared to placebo (i.e., after the first dose). OT also
attenuated craving and negative mood induced by the cue exposure. Taken together, this study
provides preliminary evidence that OT can reduce smoking craving as well as responses to cue
exposure in smokers. These findings provide an important link between preclinical and clinical
studies aimed at examining the effectiveness of OT as a novel treatment for drug craving.
This research was supported by the University of Chicago Comprehensive Cancer Center Pilot
Grant and T32MH020065.
(1) Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago IL USA
(2) Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL USA
Melissa A. Miller | [email protected]
ECO-HAB - FULLY AUTOMATED AND ECOLOGICALLY RELEVANT
ASSESSMENT OF SOCIAL IMPAIREMNTS IN MOUSE MODELS OF AUTISM
Puścian, Alicja (1) | Łęski , Szymon (1) | Winiarski, Maciej (1) | Boguszewski, Paweł (1) |
Kasprowicz, Grzegorz (2,3) | Knapska, Ewelina (1)
Impairments of social interactions are a key feature of autism spectrum disorders. Although
there exist behavioral assays designed for evaluation of conspecific-related behavior in mice,
available tasks do not allow for longitudinal observations of spontaneous interactions between
littermates. Furthermore, the experiments are usually carried out on isolated animals and
require their handling by an experimenter. These factors may exert confounding, anxietyrelated effects on obtained data and result in large between-laboratory variability. In order to
alleviate these problems, we designed Eco-HAB - a fully automated, stress-reducing tool for the
assessment of voluntary social interactions in group-housed mice. Using Eco-HAB, we assessed
social approach of valproate-treated BALB/c and C57BL/6 mice (in utero exposure to this drug
is one of pharmacological models of autistic phenotype) and Fmr1 knock-out mice (expansion
of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 gene is the most
widespread single-gene cause of autism). We determined that despite previously documented
deficits of place learning (BALB/c) and repetitive behaviors (C57BL/6), none of valproatetreated models displays impairments in social interactions. Moreover, we observed significant
enhancement in behaviors oriented towards olfactory stimuli of the conspecific-provenience.
These data are consistent with the results obtained with three-chambered apparatus test,
performed in stress-reduced conditions. On the other hand, Fmr1knock-out subjects exhibited
disrupted pattern of social stimulus approaching. We argue that when utilizing mouse models
of autism for developing therapeutic strategies, one should focus on particular behavioral
impairments, corresponding to individual symptoms in patients, rather than try to address a
rarely appearing all-inclusive phenotype. Eco-HAB enables such research, asserts high reliability
and reproducibility. It imitates natural habitat by taking into account specific features of
murine behavior. Therefore, we claim that Eco-HAB is a valuable and reliable tool for the
assessment of social interactions and gathering knowledge of functional relations in-group
housed mice.
(1) Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland | (2)
Center for Theoretical Physics, Polish Academy of Sciences, Warsaw, Poland | (3) Warsaw University of
Technology, Institute of Electronic Systems, Warsaw, Poland
Puścian Alicja | [email protected]
HEARING THE SOUND OF FOOTSTEPS AFFECTS LOCOMOTION: A STUDY
ON COCHLEAR-IMPLANTED INDIVIDUALS
Camponogara, Ivan (1) | Turchet, Luca (2) | Carner, Marco (3) | Marchioni, Daniele (3) |
Cesari, Paola (1)
Sounds are relevant in guiding movements and the sounds produced by actions evoke in the
listener movement-related motor plans. But what’s happens when the sounds are no longer
available? Here we measured the patter of walking in cochlear-implanted patients having their
sound system on or off. Moreover, in order to test how developed is for cochlear implanted
individuals the ability to discern among sounds they were asked to walk by wearing special pair
of shoes. The shoes were equipped with sensors connected to headphones that returned the
sound of stepping as if individuals were walking on a snow surface. Results showed a significant
locomotion’s change when the cochlear system was on compared to when it was off by showing
that the presence or the non-presence of the sound of the steps requires a different control of
the movements. Moreover, individuals inadvertently changed their walking pattern accordingly
as if they were actually walking on a snow surface. Results sustain both, the relevance of sound
in movement execution and the goodness of cochlear systems in discerning fine differences in
the sound of actions.
(1) Neurological and movement sciences department - Univeristy of Verona - Italy | (2) Department of
Architecture - Design & Media Technology | (3) ENT Dept. Hospital University of Verona - Verona Italy
Carner, Marco | [email protected]

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